KR102312619B1 - Composition for preventing, improving or treating cancer comprising ARL6IP5 protein as effective component - Google Patents
Composition for preventing, improving or treating cancer comprising ARL6IP5 protein as effective component Download PDFInfo
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- KR102312619B1 KR102312619B1 KR1020200125376A KR20200125376A KR102312619B1 KR 102312619 B1 KR102312619 B1 KR 102312619B1 KR 1020200125376 A KR1020200125376 A KR 1020200125376A KR 20200125376 A KR20200125376 A KR 20200125376A KR 102312619 B1 KR102312619 B1 KR 102312619B1
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- cancer
- arl6ip5
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Abstract
Description
본 발명은 ARL6IP5(ADP ribosylation factor like GTPase 6 interacting protein 5) 단백질을 유효성분으로 함유하는 암의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for the prevention, improvement or treatment of cancer containing ARL6IP5 (ADP ribosylation factor like GTPase 6 interacting protein 5) protein as an active ingredient.
암은 인류의 지난 수십 년간의 부단한 노력에도 불구하고 난치병 중의 하나로 여전히 남아 있다. 암은 인류의 건강을 위협하는 최대의 질병 중의 하나로서 세포가 일련의 돌연변이 과정을 거쳐, 무제한적이고, 비-조절적 방식으로 증식 및 불사화되어 발생하는 질병이다. 암과 관련된 다양한 생화학적 기전이 규명되어 그에 따른 치료제가 개발되어 오고 있으나, 아직까지 근본적인 치료방법은 제시되지 않고 있다.Cancer is still one of the incurable diseases despite the ceaseless efforts of mankind over the past decades. Cancer is one of the biggest diseases that threaten human health, and is a disease caused by cells undergoing a series of mutational processes to proliferate and immortalize in an unrestricted and non-controlled manner. Various biochemical mechanisms related to cancer have been identified and therapeutic agents have been developed. However, a fundamental treatment method has not yet been proposed.
이에 따라 암과 관련된 다양한 생체 내 분자의 동정 및 상기 분자를 표적으로 하는 약물의 개발에 대한 요구가 계속되고 있으며, 상기 약물 중 일부를 조합하여 암의 치료 효과를 증진하기 위한 노력 또한 계속되고 있다. 최근에 암세포생물학, 의약, 화학 등의 제반 학문의 눈부신 발전과 더불어 탁솔, 라파마이신 및 17-알릴아미노젤다나마이신(17-allylaminogeldanamycin; 17-AAG)과 같은 다수의 항암제들이 개발되었으며, 글리벡(Gleevec)과 같은 새로운 작용 기전을 가진 항암제가 개발되고 있다.Accordingly, there is a continuing demand for identification of various in vivo molecules related to cancer and development of drugs targeting the molecules, and efforts to enhance the therapeutic effect of cancer by combining some of the drugs are also continuing. In recent years, with the remarkable development of cancer cell biology, medicine, and chemistry, a number of anticancer drugs such as taxol, rapamycin, and 17-allylaminogeldanamycin (17-AAG) have been developed, and Gleevec ), anticancer drugs with a new mechanism of action are being developed.
한편, 한국공개특허 제2016-0114381호에는 'CysA5W 펩타이드를 유효성분으로 함유하는 암 예방 또는 치료용 약학 조성물'이 개시되어 있고, 한국등록특허 제1540319호에는 'cyb5R3 유전자 또는 단백질을 유효성분으로 포함하는 암 예방 및 치료용 약학적 조성물'이 개시되어 있으나, 본 발명의 ARL6IP5 단백질을 유효성분으로 함유하는 암의 예방, 개선 또는 치료용 조성물에 대해서는 기재된 바가 없다.Meanwhile, Korea Patent Application Publication No. 2016-0114381 discloses 'a pharmaceutical composition for preventing or treating cancer containing CysA5W peptide as an active ingredient', and Korean Patent No. 1540319 includes 'cyb5R3 gene or protein as an active ingredient. A pharmaceutical composition for preventing and treating cancer is disclosed, but there is no description of a composition for preventing, improving or treating cancer containing the ARL6IP5 protein of the present invention as an active ingredient.
본 발명은 상기와 같은 요구에 의해 도출된 것으로서, 본 발명자들은 ARL6IP5(JWA) 재조합 단백질을 난소암, 대장암, 전립선암 및 자궁경부암 세포주에 처리한 결과, 기존 항암제인 시스플라틴 및 올라파립에 비해 ARL6IP5 재조합 단백질이 암 세포주의 증식을 현저하게 억제시키는 것을 확인함으로써, 본 발명을 완성하였다.The present invention was derived by the above requirements, and the present inventors treated the ARL6IP5 (JWA) recombinant protein in ovarian, colorectal, prostate and cervical cancer cell lines. By confirming that the recombinant protein significantly inhibits the proliferation of cancer cell lines, the present invention was completed.
상기 과제를 해결하기 위해, 본 발명은 ARL6IP5(ADP ribosylation factor like GTPase 6 interacting protein 5) 단백질 또는 상기 ARL6IP5 단백질을 암호화하는 폴리뉴클레오티드를 포함하는 벡터를 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer containing, as an active ingredient, a vector comprising an ADP ribosylation factor like GTPase 6 interacting protein 5 (ARL6IP5) protein or a polynucleotide encoding the ARL6IP5 protein. provides
또한, 본 발명은 ARL6IP5 단백질을 유효성분으로 함유하는 항암보조제용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for anticancer adjuvant containing ARL6IP5 protein as an active ingredient.
본 발명의 ARL6IP5(JWA) 재조합 단백질은 치료가 어려운 난소암, 대장암, 전립선암 또는 자궁경부암 세포에 대해서 우수한 세포 증식 억제 효과를 나타내므로 항암제로 유용하게 활용될 수 있을 것이며, 기존 항암제와의 병용 투여를 통해 항암 효과 증대를 기대할 수 있을 것이다.The ARL6IP5 (JWA) recombinant protein of the present invention shows an excellent cell proliferation inhibitory effect on difficult-to-treat ovarian cancer, colon cancer, prostate cancer or cervical cancer cells, so it may be usefully utilized as an anticancer agent, and in combination with existing anticancer agents It can be expected to increase the anticancer effect through administration.
도 1은 ARL6IP5 재조합 단백질의 SKOV-3 (난소암 세포주)에 대한 세포 증식 억제 효과를 분석한 결과이다.
도 2는 ARL6IP5 재조합 단백질의 SKOV-3에 대한 세포사멸 효과를 분석한 결과이다. *: p < 0.05, control 그룹과 비교; #: p < 0.05, scramble 그룹과 비교.
도 3은 ARL6IP5 재조합 단백질, 시스플라틴 및 올라파립 단독 또는 이들의 병용 처리에 따른 SKOV-3의 세포사멸률을 분석한 결과이다.
도 4는 ARL6IP5 재조합 단백질, 시스플라틴 및 올라파립 단독 또는 이들의 병용 처리에 따른 HT-29 (대장암 세포주)의 세포 증식 억제 효과를 분석한 결과이다.
도 5는 ARL6IP5 재조합 단백질, 시스플라틴 및 올라파립 단독 또는 이들의 병용 처리에 따른 HT-29의 세포사멸률을 분석한 결과이다.
도 6은 ARL6IP5 재조합 단백질, 시스플라틴 및 올라파립 단독 또는 이들의 병용 처리에 따른 DU145 (전립선암 세포주)의 세포 증식 억제 효과를 분석한 결과이다.
도 7은 ARL6IP5 재조합 단백질, 시스플라틴 및 올라파립 단독 또는 이들의 병용 처리에 따른 DU145의 세포사멸률을 분석한 결과이다.
도 8은 ARL6IP5 재조합 단백질, 시스플라틴 및 올라파립 단독 또는 이들의 병용 처리에 따른 HeLa (자궁경부암 세포주)의 세포 증식 억제 효과를 분석한 결과이다.
도 9는 ARL6IP5 재조합 단백질, 시스플라틴 및 올라파립 단독 또는 이들의 병용 처리에 따른 HeLa의 세포사멸률을 분석한 결과이다.
도 10은 3D 모델을 구축한 난소암(SKOV-3), 대장암(HT-29), 전립선암(DU145), 자궁경부암(HeLa) 세포에 시스플라틴, 올라파립, ARL6IP5 RP를 처리한 후 암 세포의 형태와 크기 변화를 보여준다. control: DMSO 처리, scale bar=100 ㎛.
도 11은 3D 모델을 구축한 난소암(SKOV-3), 대장암(HT-29), 전립선암(DU145), 자궁경부암(HeLa) 세포에 시스플라틴, 올라파립, ARL6IP5 RP를 처리한 후 형성된 암세포주의 크기 변화를 측정한 결과이다. control: DMSO 처리.
도 12는 3D 모델을 구축한 난소암(SKOV-3), 대장암(HT-29), 전립선암(DU145), 자궁경부암(HeLa) 세포에 시스플라틴, 올라파립, ARL6IP5 RP를 처리한 후 세포생존률을 분석한 결과이다. control: DMSO 처리.1 is a result of analyzing the cell proliferation inhibitory effect of ARL6IP5 recombinant protein on SKOV-3 (ovarian cancer cell line).
2 is a result of analyzing the apoptosis effect of ARL6IP5 recombinant protein on SKOV-3. *: p < 0.05, compared with control group; #: p < 0.05, compared to the scramble group.
3 is a result of analyzing the cell death rate of SKOV-3 according to ARL6IP5 recombinant protein, cisplatin and olaparib alone or a combination treatment thereof.
4 is a result of analyzing the cell proliferation inhibitory effect of HT-29 (colon cancer cell line) according to ARL6IP5 recombinant protein, cisplatin and olaparib alone or a combination thereof.
5 is a result of analyzing the apoptosis rate of HT-29 according to ARL6IP5 recombinant protein, cisplatin and olaparib alone or a combination treatment thereof.
6 is a result of analyzing the cell proliferation inhibitory effect of DU145 (prostate cancer cell line) according to ARL6IP5 recombinant protein, cisplatin and olaparib alone or a combination thereof.
7 is a result of analyzing the apoptosis rate of DU145 according to ARL6IP5 recombinant protein, cisplatin and olaparib alone or a combination treatment thereof.
8 is a result of analyzing the cell proliferation inhibitory effect of HeLa (cervical cancer cell line) by treatment with ARL6IP5 recombinant protein, cisplatin and olaparib alone or in combination.
9 is a result of analyzing the apoptosis rate of HeLa according to ARL6IP5 recombinant protein, cisplatin and olaparib alone or a combination treatment thereof.
Figure 10 is ovarian cancer (SKOV-3), colorectal cancer (HT-29), prostate cancer (DU145), cervical cancer (HeLa) cells constructed 3D model after treatment with cisplatin, olaparib, ARL6IP5 RP cancer cells shows changes in shape and size. control: DMSO treatment, scale bar=100 μm.
11 is a 3D model of ovarian cancer (SKOV-3), colorectal cancer (HT-29), prostate cancer (DU145), cervical cancer (HeLa) cells formed after treatment with cisplatin, olaparib, ARL6IP5 RP It is the result of measuring the change in the size of the attention. control: DMSO treatment.
12 is a 3D model of ovarian cancer (SKOV-3), colorectal cancer (HT-29), prostate cancer (DU145), cervical cancer (HeLa) cells after treatment with cisplatin, olaparib, ARL6IP5 RP cell viability is the result of the analysis. control: DMSO treatment.
본 발명의 목적을 달성하기 위하여, 본 발명은 ARL6IP5(ADP ribosylation factor like GTPase 6 interacting protein 5) 단백질 또는 상기 ARL6IP5 단백질을 암호화하는 폴리뉴클레오티드를 포함하는 벡터를 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the object of the present invention, the present invention provides a vector comprising an ADP ribosylation factor like GTPase 6 interacting protein 5 (ARL6IP5) protein or a polynucleotide encoding the ARL6IP5 protein as an active ingredient for the prevention or treatment of cancer A pharmaceutical composition is provided.
ARL6IP5은 PRA1(Prenylated rab acceptor) 패밀리 단백질로서 인간에서 ARL6IP5 유전자에 의해 코딩되는 단백질로, ARL6IP5 단백질을 암 세포에 처리하면 암 세포의 세포증식이 억제되는 효과가 있으며, 기존 항암제인 시스플라틴(cisplatin) 및 올라파립(olaparib)에 비해 암 세포의 증식 억제 효과가 우수한 것으로 확인되었다.ARL6IP5 is a protein of the Prenylated rab acceptor (PRA1) family that is encoded by the ARL6IP5 gene in humans. When ARL6IP5 protein is treated with cancer cells, it has the effect of inhibiting the cell proliferation of cancer cells. It was confirmed that the cancer cell proliferation inhibitory effect was superior to that of olaparib.
본 발명에 따른 ARL6IP5 단백질의 범위는 서열번호 1로 표시되는 아미노산 서열을 갖는 단백질 및 이의의 기능적 동등물을 포함한다. "기능적 동등물"이란 아미노산의 부가, 치환 또는 결실의 결과, 상기 서열번호 1로 표시되는 아미노산 서열과 적어도 70% 이상, 바람직하게는 80% 이상, 더 바람직하게는 90% 이상, 더욱 바람직하게는 95% 이상의 서열 상동성을 갖는 것으로, 서열번호 1로 표시되는 단백질과 실질적으로 동질의 생리활성을 나타내는 단백질을 말한다. "실질적으로 동질의 생리활성"이란 암 예방 또는 치료에 대한 활성을 의미한다.The scope of the ARL6IP5 protein according to the present invention includes a protein having the amino acid sequence shown in SEQ ID NO: 1 and functional equivalents thereof. "Functional equivalent" means at least 70% or more, preferably 80% or more, more preferably 90% or more, more preferably the amino acid sequence represented by SEQ ID NO: 1 as a result of addition, substitution or deletion of amino acids. It refers to a protein having a sequence homology of 95% or more, and exhibiting substantially the same physiological activity as the protein represented by SEQ ID NO: 1. "Substantially homogenous physiological activity" means an activity for the prevention or treatment of cancer.
본 발명의 암 예방 또는 치료용 약학 조성물에서, 상기 암은 난소암, 대장암, 전립선암, 자궁경부암, 후두암, 폐암, 췌장암, 간암, 위암, 설암, 피부암, 뇌종양, 자궁암, 유방암, 신장암, 담낭암, 구강암, 결장암, 간암 및 방광암으로 이루어진 군으로부터 선택되는 것일 수 있고, 바람직하게는 난소암, 대장암, 전립선암 또는 자궁경부암일 수 있으나, 이에 제한되지 않는다.In the pharmaceutical composition for preventing or treating cancer of the present invention, the cancer is ovarian cancer, colon cancer, prostate cancer, cervical cancer, laryngeal cancer, lung cancer, pancreatic cancer, liver cancer, stomach cancer, tongue cancer, skin cancer, brain tumor, uterine cancer, breast cancer, kidney cancer, It may be selected from the group consisting of gallbladder cancer, oral cancer, colon cancer, liver cancer and bladder cancer, preferably ovarian cancer, colon cancer, prostate cancer or cervical cancer, but is not limited thereto.
본 발명의 암 예방 또는 치료용 약학 조성물에서, 상기 ARL6IP5 단백질을 암호화하는 폴리뉴클레오티드를 포함하는 벡터는 재조합 바이러스 벡터, 플라스미드 벡터, 코스미드 벡터 또는 박테리오파아지 벡터일 수 있으며, 바람직하게는 플라스미드 벡터인 것이지만, 이에 제한되는 것은 아니다. 또한, 상기 재조합 바이러스는 아데노바이러스, 아데노 부속 바이러스(adeno-associated virus), 레트로바이러스, 헤르페스 심플렉스 바이러스 및 렌티바이러스로 이루어진 군으로부터 선택되는 어느 하나일 수 있으나, 이에 제한되는 것은 아니다.In the pharmaceutical composition for preventing or treating cancer of the present invention, the vector containing the polynucleotide encoding the ARL6IP5 protein may be a recombinant viral vector, a plasmid vector, a cosmid vector or a bacteriophage vector, preferably a plasmid vector, but , but is not limited thereto. In addition, the recombinant virus may be any one selected from the group consisting of adenovirus, adeno-associated virus, retrovirus, herpes simplex virus and lentivirus, but is not limited thereto.
본 발명의 ARL6IP5 단백질을 포함하는 약학 조성물은 상기 유효성분 이외에 시스플라틴 및 올라파립 중 하나 이상을 추가로 포함할 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition comprising the ARL6IP5 protein of the present invention may further include at least one of cisplatin and olaparib in addition to the active ingredient, but is not limited thereto.
본 발명의 ARL6IP5 단백질을 포함하는 약학 조성물은 상기 유효성분 이외에 약학적으로 허용가능한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The pharmaceutical composition comprising the ARL6IP5 protein of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient.
본 발명에 따른 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 외용제, 좌제 및 주사제의 형태로 제형화하여 사용될 수 있다. 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 포함한 다양한 화합물 혹은 혼합물을 들 수 있다.The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., suppositories and injections, respectively, according to conventional methods. Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, and the like.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다.In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, Witepsol, Macrogol, Tween 61, cacao butter, laurin, glycerogelatin, etc. may be used.
또한, 본 발명에 따른 약학 조성물의 약학적 투여 형태는 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 조합으로 사용될 수 있다. 상기 타 약학적 활성 화합물은 이에 한정되는 것은 아니나, 시스플라틴(cisplatin), 올라파립(olaparib), 독소루비신(doxorubicin), 에토포사이드(etoposide), 파클리탁셀(paclitaxel), 도세탁셀(doxetaxel), 불소피리미딘(fluoropyrimidine), 옥살리플라틴(oxalplatin), 캄토테칸(campthotecan), 벨로테칸(Belotecan), 포도필록톡신(podophyllotoxin), 황산빈블라스틴(vinblastine sulfate), 사이클로포스파마이드(cyclophosphamide), 악티노마이신(actinomycin), 빈크리스틴 황산염(vincristine sulfate), 메토트렉세이트(methotrexate), 베바시주맙(bevacuzum ab), 탈리도마이드(thalidomide), 엘로티닙(eriotinib), 게피티닙(gefitinib), 캠토세신(camptothecin), 타목시펜(Tamoxifen), 아나스테로졸(Anasterozole), 글리벡(Gleevec), 5-플루오로우라실(5-FU), 플록슈리딘(Floxuridine), 류프로리드(Leuprolide), 플로타미드(Flutamide), 졸레드로네이트(Zoledronate), 빈크리스틴(Vincristine), 젬시타빈(Gemcitabine), 스트렙토조토신(Streptozocin), 카보플라틴(Carboplatin), 토포테칸(Topotecan), 이리노테칸(Irinotecan), 비노렐빈(Vinorelbine), 히도록시우레아(hydroxyurea), 발루비신(Valrubicin), 메클로레타민(Meclorethamine), 클로람부실(Chlorambucil), 부술판(Busulfan), 독시플루리딘(Doxifluridine), 빈블라스틴(Vinblastin), 마이토마이신(Mitomycin), 프레드니손(Prednisone), 테스토스테론(Testosterone), 미토산트론(Mitoxantron), 살리실레이트(salicylates), 나프로센(naproxen), 페노프로펜(fenoprofen), 인도메타신(indomethacin), 페닐부타존(phenyltazone), 메클로에타민(mechlorethamine), 덱사메타손(dexamethasone), 프레드니솔론(prednisolone), 셀레콕시브(celecoxib), 발데콕시브(valdecoxib), 니메슐리드(nimesulide), 코르티손(cortisone) 및 코르티코스테로이드(corticosteroid)으로 이루어진 군으로부터 선택되는 것일 수 있다.In addition, the pharmaceutical dosage form of the pharmaceutical composition according to the present invention may be used alone or in combination with other pharmaceutically active compounds, as well as suitable combinations. The other pharmaceutically active compounds include, but are not limited to, cisplatin, olaparib, doxorubicin, etoposide, paclitaxel, docetaxel, fluoropyrimidine ), oxalplatin, campthotecan, belotecan, podophyllotoxin, vinblastine sulfate, cyclophosphamide, actinomycin, vincristine sulfate, methotrexate, bevacuzumab (bevacuzum ab), thalidomide (thalidomide), erlotinib (eriotinib), gefitinib (gefitinib), camptothecin (tamoxifen), Anasterozole, Gleevec, 5-fluorouracil (5-FU), floxuridine, leuprolide, flutamide, zoledronate ( Zoledronate), Vincristine, Gemcitabine, Streptozotocin, Carboplatin, Topotecan, Irinotecan, Vinorelbine, Hydoxyurea ( hydroxyurea), Valrubicin, Meclorethamine, Chlorambucil, Busulfan, Doxifluridine, Vinblastin, Mitomycin ), Prednisone, Testosterone, Mitoxantrone, Salicylate (sal) icylates), naproxen, fenoprofen, indomethacin, phenyltazone, mechlorethamine, dexamethasone, prednisolone, celery It may be selected from the group consisting of coxib (celecoxib), valdecoxib (valdecoxib), nimesulide, cortisone and corticosteroids.
본 발명의 상기 약학 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 따라서 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명의 약학 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다.The preferred dosage of the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the severity of the disease, the drug form, the administration route, and the duration, but may be appropriately selected by those skilled in the art. Therefore, the above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes.
본 발명은 또한, ARL6IP5(ADP ribosylation factor like GTPase 6 interacting protein 5) 단백질을 유효성분으로 함유하는 항암보조제용 건강기능식품을 제공한다.The present invention also provides a health functional food for anticancer adjuvant containing ARL6IP5 (ADP ribosylation factor like GTPase 6 interacting protein 5) protein as an active ingredient.
본 발명의 일 구현 예에 따른 항암보조제용 건강기능식품에서, 상기 ARL6IP5 단백질은 서열번호 1의 아미노산 서열로 이루어진 것일 수 있으며, 구체적인 범위는 전술한 것과 같다.In the health functional food for anticancer adjuvant according to an embodiment of the present invention, the ARL6IP5 protein may consist of the amino acid sequence of SEQ ID NO: 1, and the specific range is the same as described above.
또한, 본 발명의 일 구현 예에 따른 항암보조제용 건강기능식품에서, 상기 암은 난소암, 대장암, 전립선암, 자궁경부암, 후두암, 폐암, 췌장암, 간암, 위암, 설암, 피부암, 뇌종양, 자궁암, 유방암, 신장암, 담낭암, 구강암, 결장암, 간암 및 방광암으로 이루어진 군으로부터 선택되는 것일 수 있고, 바람직하게는 난소암, 대장암, 전립선암 또는 자궁경부암일 수 있으나, 이에 제한되지 않는다.In addition, in the health functional food for anticancer supplements according to an embodiment of the present invention, the cancer is ovarian cancer, colorectal cancer, prostate cancer, cervical cancer, laryngeal cancer, lung cancer, pancreatic cancer, liver cancer, stomach cancer, tongue cancer, skin cancer, brain tumor, uterine cancer , may be selected from the group consisting of breast cancer, kidney cancer, gallbladder cancer, oral cancer, colon cancer, liver cancer and bladder cancer, preferably ovarian cancer, colon cancer, prostate cancer or cervical cancer, but is not limited thereto.
본 발명의 일 구현 예에 따른 항암보조제용 건강기능식품에서, 상기 건강 기능성 식품의 종류에는 특별한 제한은 없다. 상기 ARL6IP5 단백질을 첨가할 수 있는 식품의 예로는 음료수, 차, 드링크제 및 비타민 복합제 등이 있으며, 환제, 분말, 과립, 침제, 정제, 캡슐 또는 음료인 형태로 사용할 수 있고, 통상적인 의미에서의 건강기능성식품을 모두 포함한다.In the health functional food for anticancer adjuvant according to an embodiment of the present invention, there is no particular limitation on the type of the health functional food. Examples of foods to which the ARL6IP5 protein can be added include beverages, tea, drinks, and vitamin complexes, and may be used in the form of pills, powders, granules, needles, tablets, capsules or beverages, and health in the general sense. Includes all functional foods.
상기 ARL6IP5 단백질 외에 본 발명의 건강기능성식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다.In addition to the ARL6IP5 protein, the health functional food of the present invention contains various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and salts thereof , alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples.
재료 및 방법Materials and Methods
1. ARL6IP5 과발현 세포주 제작1. Preparation of ARL6IP5 overexpressing cell line
ARL6IP5 cDNA ORF clone은 GenScript(#oHu24499, 벡터-pcDNA3.1+/C-(K)DYK, USA)로부터 구입하였다. 24-웰 플레이트에 웰 당 0.5×105 세포의 농도로 SKOV-3 세포를 분주하고 웰 면적의 80% 세포분포도를 나타낼 때 Lipofectamine 2000 시약 (#11668019, Invitrogent-Thermo Fisher Scientific, USA)으로 제조사의 지침에 따라 ARL6IP5 벡터를 형질전환시켰다. 간단하게, 1 ㎍의 pcDNA3.1/ALL6IP5 플라스미드를 함유하는 50 ㎕ 무혈청 배지를 제조하고 3 ㎕ Lipofectamine 2000을 50 ㎕ 무혈청 배지에 별도로 희석시켰다. 그 후, 두 용액을 혼합하고 잘 섞은 후, 5분 동안 배양하여 융합물을 형성시켰다. 이어서, 50 ㎕의 융합물을 각 웰에 첨가하고, 플레이트를 손으로 부드럽게 흔들어 처리 용액이 웰에 잘 분산되도록 하였다. 이어서, 세포를 48시간 동안 배양하고, 처리 용액을 정상 배양 배지로 교체하여 12시간 추가 배양하였다. 이후 세포를 회수하여, 웨스턴 블롯 분석을 통해 ARL6IP5 발현을 확인 하였다.ARL6IP5 cDNA ORF clone was purchased from GenScript (#oHu24499, vector-pcDNA3.1+/C-(K)DYK, USA). Dispense SKOV-3 cells at a concentration of 0.5×10 5 cells per well in a 24-well plate and use Lipofectamine 2000 reagent (#11668019, Invitrogent-Thermo Fisher Scientific, USA) when the cell distribution is 80% of the well area. The ARL6IP5 vector was transformed according to the instructions. Briefly, 50 μl serum-free medium containing 1 μg of pcDNA3.1/ALL6IP5 plasmid was prepared and 3 μl Lipofectamine 2000 was separately diluted in 50 μl serum-free medium. Thereafter, the two solutions were mixed, mixed well, and incubated for 5 minutes to form a fusion. Then, 50 μl of the fusion was added to each well and the plate was gently shaken by hand to ensure that the treatment solution was well dispersed in the wells. Then, the cells were cultured for 48 hours, and the treatment solution was replaced with a normal culture medium and cultured for an additional 12 hours. Thereafter, the cells were harvested, and ARL6IP5 expression was confirmed through western blot analysis.
2. ARL6IP5 재조합 단백질의 암 세포에 대한 세포 사멸능 분석2. Analysis of ARL6IP5 Recombinant Protein Apoptosis against Cancer Cells
ARL6IP5 재조합 단백질의 세포 사멸 효과를 확인하기 위해, 다양한 암 세포를 이용하여 ARL6IP5 재조합 단백질 처리에 따른 세포 증식률을 분석하였다. 구체적으로, 난소암 세포주(SKOV-3), 전립선암 세포주(DU145, ATCC® HTB-81TM), 대장암 세포주(HT-29, ATCC® HTB-38TM) 및 자궁경부암 세포주(HeLa, ATCC® CCL-2TM)를 96-웰 플레이트에 웰당 1×104 세포의 농도로 분주하여 24시간 동안 배양한 후, 배양한 세포에 인간 ARL6IP5 재조합 단백질(ARL6IP5 RP, #ARLIP5-9863H, Creative BioMart, USA), 시스플라틴(cis-Dichlorodiammine platinum(Ⅱ), #P4394, Sigma Aldrich, USA) 및 올라파립(AZD2281, #A10111-10mM-D, Adooq Bioscience, USA)을 각기 다른 농도로 처리하고 추가로 72시간 동안 배양하였다. 그 후, EZ-cytox 세포생존 분석 키트(#DLS-1906, DoGenBioCo., Ltd.)를 사용하여 세포 증식률을 측정하였다. 각 실험은 처리구당 3반복 수행되었다.In order to confirm the apoptosis effect of the ARL6IP5 recombinant protein, cell proliferation rates according to the ARL6IP5 recombinant protein treatment were analyzed using various cancer cells. Specifically, ovarian cancer cell line (SKOV-3), prostate cancer cell line (DU145, ATCC ® HTB-81 TM ), colorectal cancer cell line (HT-29, ATCC ® HTB-38 TM ) and cervical cancer cell line (HeLa, ATCC ® CCL-2 TM ) was dispensed in a 96-well plate at a concentration of 1×10 4 cells per well and cultured for 24 hours, and then human ARL6IP5 recombinant protein (ARL6IP5 RP, #ARLIP5-9863H, Creative BioMart, USA) in the cultured cells. ), cisplatin (cis-Dichlorodiammine platinum(II), #P4394, Sigma Aldrich, USA) and olaparib (AZD2281, #A10111-10mM-D, Adooq Bioscience, USA) were treated at different concentrations and for an additional 72 hours. cultured. Then, the cell proliferation rate was measured using the EZ-cytox cell viability assay kit (#DLS-1906, DoGenBioCo., Ltd.). Each experiment was performed in triplicate per treatment group.
또한, ARL6IP5 재조합 단백질 처리에 따른 세포사멸을 측정하기 위해 Hoechst 33342 염색을 수행하였다. 구체적으로, 세포(2×105 세포/웰)를 6-웰 플레이트에 이식하여 배양기에 밤새 배양하였다. 배양된 세포에 시스플라틴(20 μM), 올라파립(25 μM) 및 ARL6IP5 재조합 단백질(2.5 ㎍/㎖)을 각각 또는 병용 처리하고 37℃에서 24시간 동안 배양하였다. 배양 후, 6-웰 플레이트에 배양된 세포를 PBS로 1회 세척한 다음, 15분 동안 5 ㎍/㎖의 Hoechst 33342를 처리하였다. 마지막으로, 세포를 PBS로 2회 세척하고 역형광 현미경(Axioskop 2 plus microscope, Carl Zeiss, Germany)으로 관찰하였다. 세포사멸 핵은 중첩되지 않은 5개 영역에서 산출되었으며, 산출된 총 핵 수의 백분율로 표현되었다.In addition, Hoechst 33342 staining was performed to measure apoptosis according to ARL6IP5 recombinant protein treatment. Specifically, cells (2×10 5 cells/well) were transplanted into 6-well plates and cultured overnight in an incubator. The cultured cells were treated with cisplatin (20 μM), olaparib (25 μM) and ARL6IP5 recombinant protein (2.5 μg/ml), respectively or in combination, and incubated at 37° C. for 24 hours. After incubation, cells cultured in 6-well plates were washed once with PBS, and then treated with 5 μg/ml of Hoechst 33342 for 15 minutes. Finally, the cells were washed twice with PBS and observed under a reverse fluorescence microscope (Axioskop 2 plus microscope, Carl Zeiss, Germany). Apoptotic nuclei were counted in 5 non-overlapping regions and expressed as a percentage of the total number of nuclei counted.
3. 3D 세포 모델 구축3. Building 3D Cell Models
3-1. 단일 세포 현탁액 준비:3-1. Single cell suspension preparation:
각각의 암 세포를 트립신을 처리하여 단일 세포로 분리될 때까지 37℃에 배양하였다. 배지 2 ㎖을 첨가하여 트립신 활성을 중단시키고 5 ㎖ 피펫을 사용하여 세포액을 현탁시켰다. 세포를 15 ㎖ 튜브로 ?グ? 2,000 rpm에서 4분 동안 원심분리시켰다. 상층액을 버리고 배지 1 ㎖로 펠릿을 세척하였다. 세포를 배지 2 ㎖에 재현탁시키고 세포 수를 계수하여 2×106 세포/㎖로 준비하였다.Each cancer cell was trypsinized and cultured at 37° C. until dissociated into single cells. The trypsin activity was stopped by adding 2 ml of medium and the cell fluid was suspended using a 5 ml pipette. Cells were transferred into 15 ml tubes. Centrifuge at 2,000 rpm for 4 minutes. The supernatant was discarded and the pellet was washed with 1 ml of medium. The cells were resuspended in 2 ml of medium and the number of cells was counted to prepare 2×10 6 cells/ml.
3-2. 매달린 방울모양 형성:3-2. Forming a hanging droplet:
60 mm 조직 배양 접시에서 뚜껑을 제거하고 접시 바닥에 PBS 5 ㎖을 놓는다. 이는 수화 챔버 역할을 한다. 뚜껑을 뒤집고 피펫을 사용하여 뚜껑 바닥에 세포 현탁액 20 ㎕를 한 방울씩 떨어뜨렸다. 이 때, 각 방울끼리 서로 닿지 않도록 적정한 거리를 두고 접시당 최소 20 방울을 떨어 뜨려 놓는다. 뚜껑을 PBS로 채워진 바닥 챔버에 덮고 37℃, 5% CO2, 95% 습도 조건에서 배양하고 매일 방울 모양을 모니터링하였다. 세포 시트 또는 응집체가 형성될 때까지 배양하였다. 입체 현미경을 사용하여 응집체 형성을 평가하였다.Remove the lid from the 60 mm tissue culture dish and place 5 ml of PBS on the bottom of the dish. It acts as a hydration chamber. Invert the lid and use a pipette to drop 20 μl of the cell suspension onto the bottom of the lid. At this time, place at least 20 drops per plate at an appropriate distance so that each drop does not touch each other. The lid was covered with a bottom chamber filled with PBS, incubated at 37° C., 5% CO 2 , and 95% humidity, and the droplet shape was monitored daily. Cultured until cell sheets or aggregates were formed. Aggregate formation was assessed using stereomicroscopy.
4. 3D 세포 모델을 이용한 세포 생존율 분석4. Cell Viability Analysis Using 3D Cell Models
전술한 방법을 통해 세포 시트가 형성되면, 배지를 포함한 1% 폴리-2-하이드록실에틸메타크릴레이트(poly-2-hydroxylethyl methacrylate, poly-HEMA) 코팅 플레이트로 세포 시트를 옮기고 DMSO(대조군), 시스플라틴, 올라파립, ARL6IP5 재조합 단백질(ARL6IP5 RP)을 각각 처리하여 37℃, 5% CO2, 95% 습도 조건에서 배양하였다. 세포생존률은 EZ-cytox 세포생존 분석 키트를 사용하여 약물처리 72시간 후에 측정하였다. 3D 배양실험은 7일째 되는 날 inverted contrast microscopy로 관찰하여 촬영하였다.When a cell sheet is formed through the method described above, transfer the cell sheet to a 1% poly-2-hydroxylethyl methacrylate (poly-HEMA) coated plate containing medium, DMSO (control), Cisplatin, olaparib, ARL6IP5 recombinant protein (ARL6IP5 RP) was treated, respectively , and cultured at 37° C., 5% CO 2 , and 95% humidity conditions. Cell viability was measured 72 hours after drug treatment using the EZ-cytox cell viability assay kit. The 3D culture experiment was observed and photographed by inverted contrast microscopy on the 7th day.
실시예 1. ARL6IP5 과발현 세포의 세포 증식률 분석Example 1. Analysis of cell proliferation rate of ARL6IP5 overexpressing cells
ARL6IP5의 암 세포 증식 억제에 미치는 영향을 알아보기 위해, ARL6IP5를 과발현하는 SKOV-3 세포주를 제작한 후 생장률을 비교해 보았다. 그 결과, 도 1에 개시된 것과 같이 ARL6IP5를 과발현하는 SKOV-3 세포주(ARL6IP5++)는 일반 SKOV-3 세포주(control)에 비해 세포 증식이 감소되었음을 확인할 수 있었다. 또한, SKOV-3 세포주에 ARL6IP5의 발현을 저해시키기 위해 siRNA를 처리한 결과(siRNA_ARL6IP5), 일반 SKOV-3 세포주(control)에 비해 세포 증식이 증가됨을 알 수 있었다.In order to investigate the effect of ARL6IP5 on the inhibition of cancer cell proliferation, the growth rate was compared after the SKOV-3 cell line overexpressing ARL6IP5 was prepared. As a result, as shown in FIG. 1 , it was confirmed that the SKOV-3 cell line (ARL6IP5++) overexpressing ARL6IP5 had reduced cell proliferation compared to the general SKOV-3 cell line (control). In addition, as a result of treating the SKOV-3 cell line with siRNA to inhibit the expression of ARL6IP5 (siRNA_ARL6IP5), it was found that cell proliferation was increased compared to that of the general SKOV-3 cell line (control).
또한, ARL6IP5를 과발현하는 SKOV-3 세포주에 항암제 시스플라틴(cisplatin)을 처리한 결과, SKOV-3 세포주(control), ARL6IP5의 발현을 저해시키기 위해 siRNA를 처리한 SKOV-3 세포주(siRNA_ARL6IP5) 및 siRNA 처리 대조구 SKOV-3(scramble)에 비해 ARL6IP5를 과발현하는 SKOV-3 세포주(ARL6IP5++)에서 세포 사멸률이 가장 높은 것을 알 수 있었다(도 2). 이상의 결과를 통해, ARL6IP5가 암 세포의 증식을 억제하는 효과가 있고, 항암제에 대한 암 세포의 민감도를 증가시킴을 알 수 있었다.In addition, as a result of treating the SKOV-3 cell line overexpressing ARL6IP5 with the anticancer drug cisplatin, the SKOV-3 cell line (control), the SKOV-3 cell line treated with siRNA to inhibit the expression of ARL6IP5 (siRNA_ARL6IP5) and siRNA treatment It was found that the cell death rate was the highest in the SKOV-3 cell line (ARL6IP5++) overexpressing ARL6IP5 compared to the control SKOV-3 (scramble) ( FIG. 2 ). Through the above results, it was found that ARL6IP5 has an effect of inhibiting the proliferation of cancer cells and increases the sensitivity of cancer cells to anticancer agents.
실시예 2. 다양한 암 세포에 대한 ARL6IP5의 항암 효과 분석Example 2. Analysis of the anticancer effect of ARL6IP5 on various cancer cells
난소암(SKOV-3), 대장암(HT-29), 전립선암(DU145), 자궁경부암(HeLa) 세포에 대한 ARL6IP5의 항암 효과를 확인하기 위해서, 각각의 세포주에 ARL6IP5 재조합 단백질(ARL6IP5 RP), 시스플라틴 및 올리파립을 단독 혹은 병용 처리하여 세포 사멸률을 분석하였다. 상기 시스플라틴, 올라파립 및 ARL6IP5 RP의 처리 농도는 각각의 세포주에서 해당 약물의 50% 억제 농도를 측정하여 처리하였다(표 1).To confirm the anticancer effect of ARL6IP5 on ovarian cancer (SKOV-3), colorectal cancer (HT-29), prostate cancer (DU145), and cervical cancer (HeLa) cells, ARL6IP5 recombinant protein (ARL6IP5 RP) in each cell line , Cell death rates were analyzed by treatment with cisplatin and oliparib alone or in combination. The treatment concentrations of the cisplatin, olaparib and ARL6IP5 RP were treated by measuring the 50% inhibitory concentration of the corresponding drug in each cell line (Table 1).
그 결과, 난소암(도 3), 대장암(도 4 및 도 5), 전립선암(도 6 및 도 7) 및 자궁경부암(도 8 및 도 9) 세포 모두에 대해서 기존 항암제인 시스플라틴 및 올라파립에 비해 ARL6IP5 RP가 우수한 세포 사멸능을 가지고 있음을 확인할 수 있었다.As a result, the existing anticancer drugs cisplatin and olaparib for all of ovarian cancer (FIG. 3), colorectal cancer (FIGS. 4 and 5), prostate cancer (FIGS. 6 and 7) and cervical cancer (FIG. 8 and 9) cells It was confirmed that ARL6IP5 RP had excellent apoptosis compared to that.
실시예 3. 3D 세포 모델을 이용한 ARL6IP5의 항암 효과 분석Example 3. Analysis of anticancer effect of ARL6IP5 using 3D cell model
본 발명자는 in vivo 환경과 유사한 세포 조건을 만들기 위해, 3D 세포 모델을 구축하였다. 그 후, 3D 세포 모델을 이용하여 ARL6IP5의 항암 효과를 분석하였다.The present inventors constructed a 3D cell model to create cellular conditions similar to the in vivo environment. Then, the anticancer effect of ARL6IP5 was analyzed using a 3D cell model.
3D 모델을 구축한 난소암(SKOV-3), 대장암(HT-29), 전립선암(DU145), 자궁경부암(HeLa) 세포에 DMSO(대조군), 시스플라틴, 올라파립, ARL6IP5 RP를 각각 처리하고, 각 암 세포의 모양과 크기를 비교하였다. 항암제와 ARL6IP5 RP 처리 농도는 표 1과 같다. 그 결과, 모든 암에서 시스플라틴, 올라파립 및 ARL6IP5 RP 처리군에서 대조군 대비 3D 세포의 크기가 줄어들었음을 확인할 수 있다(도 10).DMSO (control), cisplatin, olaparib, and ARL6IP5 RP were treated in 3D model-constructed ovarian cancer (SKOV-3), colorectal cancer (HT-29), prostate cancer (DU145), and cervical cancer (HeLa) cells, respectively. , the shape and size of each cancer cell were compared. Table 1 shows the anticancer drug and ARL6IP5 RP treatment concentrations. As a result, in all cancers, it can be confirmed that the size of 3D cells was reduced in the cisplatin, olaparib and ARL6IP5 RP-treated groups compared to the control group (FIG. 10).
또한, 각 암세포의 크기를 Image J를 사용해 측정하여 그래프로 비교한 결과에서도, 모든 암에서 시스플라틴, 올라파립 및 ARL6IP5 RP 처리군에서 대조군 대비 암 세포의 크기가 감소되었음을 알 수 있었다(도 11). 특히, 난소암(SKOV-3) 및 전립선암(DU145)에서 ARL6IP5 RP 처리군이 기존 항암제인 시스플라틴 및 올라파립 처리군에 비해 암 세포의 크기가 더욱 작은 것을 알 수 있었다.In addition, the size of each cancer cell was measured using Image J and compared graphically, it was found that in all cancers, the size of cancer cells was reduced in the cisplatin, olaparib, and ARL6IP5 RP-treated groups compared to the control group (FIG. 11). In particular, it was found that in ovarian cancer (SKOV-3) and prostate cancer (DU145), the size of cancer cells was smaller in the ARL6IP5 RP-treated group compared to the existing anticancer agents cisplatin and olaparib-treated group.
또한, 세포생존률을 측정한 결과, 시스플라틴, 올라파립 및 ARL6IP5 RP 처리군에서 대조군 대비 세포생존률이 낮은 것으로 확인되었다(도 12). 특히, 올라파립과 ARL6IP5 RP 처리군이 모든 암 세포에서 세포생존률이 낮았고, ARL6IP5 RP 처리군은 난소암(SKOV-3) 및 자궁경부암(HeLa)에서 세포생존률이 가장 낮게 확인되었다.In addition, as a result of measuring the cell viability, it was confirmed that the cell viability was lower in the cisplatin, olaparib and ARL6IP5 RP-treated groups compared to the control group (FIG. 12). In particular, olaparib and ARL6IP5 RP treatment group showed low cell viability in all cancer cells, and ARL6IP5 RP treatment group had the lowest cell viability in ovarian cancer (SKOV-3) and cervical cancer (HeLa).
<110> INDUSTRY-ACADEMIC COOPERATION FOUNDATION GYEONGSANG NATIONAL UNIVERSITY inje university industry-academic cooperation foundation SAMSUNG LIFE PUBLIC WELFARE FOUNDATION <120> Composition for preventing, improving or treating cancer comprising ARL6IP5 protein as effective component <130> PN20204 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 188 <212> PRT <213> Homo sapiens <400> 1 Met Asp Val Asn Ile Ala Pro Leu Arg Ala Trp Asp Asp Phe Phe Pro 1 5 10 15 Gly Ser Asp Arg Phe Ala Arg Pro Asp Phe Arg Asp Ile Ser Lys Trp 20 25 30 Asn Asn Arg Val Val Ser Asn Leu Leu Tyr Tyr Gln Thr Asn Tyr Leu 35 40 45 Val Val Ala Ala Met Met Ile Ser Ile Val Gly Phe Leu Ser Pro Phe 50 55 60 Asn Met Ile Leu Gly Gly Ile Val Val Val Leu Val Phe Thr Gly Phe 65 70 75 80 Val Trp Ala Ala His Asn Lys Asp Val Leu Arg Arg Met Lys Lys Arg 85 90 95 Tyr Pro Thr Thr Phe Val Met Val Val Met Leu Ala Ser Tyr Phe Leu 100 105 110 Ile Ser Met Phe Gly Gly Val Met Val Phe Val Phe Gly Ile Thr Phe 115 120 125 Pro Leu Leu Leu Met Phe Ile His Ala Ser Leu Arg Leu Arg Asn Leu 130 135 140 Lys Asn Lys Leu Glu Asn Lys Met Glu Gly Ile Gly Leu Lys Arg Thr 145 150 155 160 Pro Met Gly Ile Val Leu Asp Ala Leu Glu Gln Gln Glu Glu Gly Ile 165 170 175 Asn Arg Leu Thr Asp Tyr Ile Ser Lys Val Lys Glu 180 185 <110> INDUSTRY-ACADEMIC COOPERATION FOUNDATION GYEONGSANG NATIONAL UNIVERSITY inje university industry-academic cooperation foundation SAMSUNG LIFE PUBLIC WELFARE FOUNDATION <120> Composition for preventing, improving or treating cancer comprising ARL6IP5 protein as effective component <130> PN20204 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 188 <212> PRT <213> Homo sapiens <400> 1 Met Asp Val Asn Ile Ala Pro Leu Arg Ala Trp Asp Asp Phe Phe Pro 1 5 10 15 Gly Ser Asp Arg Phe Ala Arg Pro Asp Phe Arg Asp Ile Ser Lys Trp 20 25 30 Asn Asn Arg Val Val Ser Asn Leu Leu Tyr Tyr Gln Thr Asn Tyr Leu 35 40 45 Val Val Ala Ala Met Met Met Ile Ser Ile Val Gly Phe Leu Ser Pro Phe 50 55 60 Asn Met Ile Leu Gly Gly Ile Val Val Val Leu Val Phe Thr Gly Phe 65 70 75 80 Val Trp Ala Ala His Asn Lys Asp Val Leu Arg Arg Met Lys Lys Arg 85 90 95 Tyr Pro Thr Thr Phe Val Met Val Val Met Leu Ala Ser Tyr Phe Leu 100 105 110 Ile Ser Met Phe Gly Gly Val Met Val Phe Val Phe Gly Ile Thr Phe 115 120 125 Pro Leu Leu Leu Met Phe Ile His Ala Ser Leu Arg Leu Arg Asn Leu 130 135 140 Lys Asn Lys Leu Glu Asn Lys Met Glu Gly Ile Gly Leu Lys Arg Thr 145 150 155 160 Pro Met Gly Ile Val Leu Asp Ala Leu Glu Gln Gln Glu Glu Gly Ile 165 170 175 Asn Arg Leu Thr Asp Tyr Ile Ser Lys Val Lys Glu 180 185
Claims (8)
상기 암은 난소암, 대장암, 전립선암 또는 자궁경부암인 것을 특징으로 하는 암의 예방 또는 치료용 약학 조성물.A pharmaceutical composition for preventing or treating cancer containing ARL6IP5 (ADP ribosylation factor like GTPase 6 interacting protein 5) protein as an active ingredient,
The cancer is a pharmaceutical composition for the prevention or treatment of cancer, characterized in that ovarian cancer, colorectal cancer, prostate cancer or cervical cancer.
상기 암은 난소암, 대장암, 전립선암 또는 자궁경부암인 것을 특징으로 하는 항암보조제용 건강기능식품.As a health functional food for anticancer supplements containing ARL6IP5 (ADP ribosylation factor like GTPase 6 interacting protein 5) protein as an active ingredient,
The cancer is ovarian cancer, colorectal cancer, prostate cancer, or a health functional food for an anticancer supplement, characterized in that the cervical cancer.
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| CN103239710A (en) * | 2013-05-14 | 2013-08-14 | 南京医科大学 | Polypeptide with anti-tumor activity and application thereof |
| CN110437176A (en) * | 2019-08-12 | 2019-11-12 | 周建伟 | A kind of antitumoral compounds, Its Preparation Method And Use based on activation JWA gene and the HER2 that degrades |
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| WO2012061754A2 (en) * | 2010-11-05 | 2012-05-10 | The Broad Institute, Inc. | Compounds and methods for treating autoimmune diseases |
| KR102285771B1 (en) * | 2020-03-20 | 2021-08-05 | 경상국립대학교산학협력단 | ARL6IP5 composite agent for preventing, improving or treating anticancer agent-resistant ovarian cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103239710A (en) * | 2013-05-14 | 2013-08-14 | 南京医科大学 | Polypeptide with anti-tumor activity and application thereof |
| CN110437176A (en) * | 2019-08-12 | 2019-11-12 | 周建伟 | A kind of antitumoral compounds, Its Preparation Method And Use based on activation JWA gene and the HER2 that degrades |
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