CN113683703A - hTERT target substance and application thereof - Google Patents
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Abstract
The invention discloses a targeting substance of hTERT, which has the function of antagonizing the interaction of hTERT and a subunit ND1 protein of a mitochondrial respiratory chain complex I (complex I), wherein the targeting substance is a peptide containing an amino acid sequence FMAEY (SEQ ID NO:1), and is preferably a membrane penetrating peptide containing a membrane penetrating sequence. Also discloses application of the target in preparing a modulator for antagonizing hTERT/ND1 protein interaction, and the target enhances the sensitivity of tumor cells to chemotherapeutic drugs by enhancing the oxidative phosphorylation of mitochondria of drug-resistant tumor cells.
Description
Technical Field
The invention relates to a peptide and application thereof, in particular to a human telomerase reverse transcriptase target and application thereof in preparing a regulator for enhancing tumor cell chemotherapy sensitivity.
Background
Human Telomerase (Telomerase) is responsible for lengthening telomeres in cells, is a reverse transcriptase in nature, can fill up telomeres lost in DNA replication, and plays an important role in maintaining chromosome stability and cell activity. Elizabeth Blackburn, Carol Greider and Jack Szostak won the 2009 nobel prize for physiology or medicine due to the superior contribution in telomeres and telomerase. Human telomerase reverse transcriptase (hTERT) is the core catalytic subunit of human telomerase and plays an important role in tumorigenesis and progression by maintaining telomere length, enhancing telomere activity, promoting tumor proliferation, invasive metastasis and resisting apoptosis (Harley cb. telomerase and cancer therapeutics. nat Rev cancer.2008,8(3): 167-79.). The hTERT is mainly positioned in a nucleus, and a recent research result shows that the hTERT can also be positioned in mitochondria; in addition, hTERT can exert its oncogenic effect independent of its classical telomerase reverse transcriptase activity. For example, it has been shown that hTERT can promote the degradation of FoxO3a by interacting with MDM2, thereby up-regulating ITGB1 to promote gastric cancer invasion and metastasis (Hu C, Ni Z, Li BS, et al hTERT proteins by stimulating FoxO3a ubiquitin and subsequent ITGB1 upper regulation. gut.2017,66(1): 31-42).
The crystal structure of hTERT is not completely resolved at present, and the current understanding of TERT structure mainly comes from pseudoerythro-castanea (t. castaneum), wherein TERT structure comprises TRBD, fingers, palm and thumb, etc. four important domains (Mitchell M, Gillis a, Futahashi M, et al. structural barbassis for molecular biology filing to rnatplate and molecular dna. nat structural Mol biol.2010,17(4): 513-8.). Schematic diagram of the main structure of castaneum TERT is shown in fig. 1.
Under the action of stress stimulation, hTERT in tumor cells can be translocated to mitochondria, and after the hTERT enters the mitochondria, the hTERT can inhibit the oxidative phosphorylation of the mitochondria and promote the survival of the tumor cells and the resistance of chemotherapy. However, it is not clear at present how hTERT translocating to mitochondria affects mitochondrial metabolism and its specific resistance mechanism under the action of chemotherapeutic drugs; meanwhile, targeted intervention and translocation to hTERT of tumor cell mitochondria are carried out, so that mitochondrial function is restored, and a treatment strategy for reversing drug resistance of tumor cells is still blank at present. Therefore, the method has important significance for exploring the specific mechanism of hTERT mitochondrial translocation for resisting chemotherapeutic drugs, searching an intervention target point and searching a solution aiming at the target point so as to enhance the sensitivity of tumor cells to the chemotherapeutic drugs.
Disclosure of Invention
One of the purposes of the invention is to provide an hTERT target.
A hTERT target, which is characterized in that the target has the function of antagonizing the protein interaction of human telomerase reverse transcriptase (hTERT) and subunit MT-ND1 (ND 1) of mitochondrial respiratory chain complex I (complete I), and the target is a peptide comprising amino acid sequence FMAEY (SEQ ID NO: 1).
Preferably, the above peptide comprises amino acid sequence GPFALFFMAEYT (SEQ ID NO: 2).
Preferably, the peptide further comprises a transmembrane sequence.
Preferably, the transmembrane sequence is YGRKKRRQRRR (SEQ ID NO: 3).
Preferably, the amino acid sequence of the above-mentioned targeting agent is YGRKKRRQRRRGPFALFFMAEYT (SEQ ID NO: 4).
The second objective of the present invention is to provide a method for synthesizing the above-mentioned target.
The key point of the method for synthesizing the target substance is that the target substance is synthesized by a polypeptide solid-phase synthesis method.
The invention also aims to provide the application of the target of human telomerase reverse transcriptase (hTERT) in the preparation of a regulator for antagonizing hTERT/ND1 protein interaction.
Preferably, the hTERT is mitochondrially localized hTERT in tumor cells.
Preferably, the tumor cell is resistant to a chemotherapeutic agent, and the modulator has an effect of increasing the sensitivity of the tumor cell to the chemotherapeutic agent.
Preferably, the modulator increases the sensitivity of the tumor cell to the chemotherapeutic agent by increasing mitochondrial oxidative phosphorylation.
Preferably, the chemotherapeutic agent is Cisplatin (CDDP) or other platinum-based agent.
The fourth object of the present invention is to provide a regulator.
A modulator, the key to which is contained any one of the above-described targets.
Drawings
Fig. 1 is a schematic diagram of the main structure of t.castaneum TERT;
FIG. 2 shows the key amino acid sequences of various hTERT vectors and the TRAP experimental results, wherein Control is hTERTWTAnd hTERTDNControl groups of groups, Negative Control and TSR8 are Negative and positive controls, respectively;
FIG. 3 shows the Western Blot result of mitochondrial hTERT content in CDDP-resistant HCC cells and parental cells;
FIG. 4 is the Co-IP results of detecting the protein interaction of hTERT with HA-ND 1;
FIG. 5 shows the results of immunofluorescence-validated interaction of hTERT with ND1 protein;
FIG. 6 is a schematic biological structure of ND 1;
FIG. 7 shows partial amino acid sequences of ND1 from different species, human (human), mouse (mouse), rat (rat), chicken (chicken), frog (frog), fish (fish) and fly (fly), all of which comprise FMAEY or FLAEY sequences;
FIG. 8 shows the results of Co-IP assay to determine the effect of the cell-penetrating peptide on the interaction of hTERT with HA-ND1 protein;
FIG. 9 shows the transmembrane peptide TAT-Pep vs. Huh7 hTERTDNThe effects of cellular ATP production;
FIG. 10 is a graph of the effect of the cell-penetrating peptide TAT-Pep on the half inhibitory concentration (IC50) of Huh7 CDDP-R cells.
Chinese and English noun comparison:
telomerase reverse transcriptase, TERT; human telomerase reverse transcriptase, hTERT; mitochondrial respiratory chain Complex I, Complex I; hepatocellular carcinoma, HCC; western immunoblotting, Western Blot, WB; Co-Immunoprecipitation, Co-IP; immunoprecipitation, IP; telomere repeat amplification assay, TRAP; adenosine triphosphate, ATP; CDDP-resistant Huh7 cells, Huh7 CDDP-R; stably transfected cells overexpressing wild-type hTERT, hTERTWTA cell; stably transfected cells overexpressing telomerase reverse transcriptase mutant hTERT, hTERTDNA cell; stably transfected cell over-expressing telomerase reverse transcriptase activity and mitochondrial localization sequence mutant hTERT, hTERTNUCA cell; median inhibitory concentration, IC 50; cisplatin, CDDP.
Detailed Description
The invention is further illustrated by the following examples and figures.
First, experimental material
(1) Cell: human hepatoma cell (HCC cell) Huh7 was purchased from cell resource center of Shanghai Life sciences research institute of Chinese academy of sciences; cisplatin (CDDP) -resistant Huh7 cells (Huh7 CDDP-R) were purchased from Hill, Wen Biotech, Inc., Shanghai;
(2) hTERT type ii lentiviral vectors: purchased from Chongqing Ribes Biotechnology, Inc.;
hTERTWTfor stably transfected cells overexpressing wild-type hTERT, hTERTDNhTERT, a stably transfected cell that overexpresses hTERT having mutant telomerase reverse transcriptase activityNUCIs a stable transfected cell over-expressing telomerase reverse transcriptase activity and a mitochondrial localization sequence mutant hTERT; the key amino acid sequences of the respective vectors are shown in FIG. 2. TRAP experiment confirmed Huh7 hTERTWTAnd Huh7 hTERTDNThe construction of stably transfected cell lines was successful, see FIG. 2.
(3) The HA-ND1 overexpression plasmid vector is purchased from Changsha Youbao biotechnology limited and is an overexpression vector for fusion expression of an HA tag and an ND1 molecule.
(4) Lysates for western immunoblotting (WB) and Co-immunoprecipitation (Co-IP): purchased from bio-technology limited, Jiangsu Biyuntian;
(5) protease inhibitor Cocktail: purchased from Roche, switzerland;
(6) BCA protein concentration determination kit: purchased from bio-technology limited, Jiangsu Biyuntian;
(7) hTERT antibody, HA antibody: purchased from Abcam, Inc., USA;
HSP60 antibody: purchased from CST corporation, USA;
secondary antibody: purchased from sequoia Jinqiao biotech, Inc. in Beijing;
(8) Co-IP kit: purchased from Active Motif, usa;
(9) mitochondrial extraction kit: purchased from QIAGEN, germany;
(10) CCK-8 cell activity detection kit: purchased from bio-technology limited, Jiangsu Biyuntian;
(11) adenosine Triphosphate (ATP) assay kit: purchased from bio-technology limited, Jiangsu Biyuntian;
(12) RNA Affinity Purification (TRAP) detection kit: purchased from Millipore corporation, usa;
(13) mass spectrometry services: shanghai Zhongke New Life Biotechnology, Inc.;
second, experiment
Example 1
Interaction of hTERT with ND1
1.1 mitochondrial hTERT content in drug resistant cells
The mitochondrial hTERT content in a cis-platinum-resistant HCC cell (CDDP-R) and a parent cell (Control) is detected by taking a human hepatocyte liver cancer (HCC) cell Huh7 as a model.
Mitochondrial proteins of Huh7 CDDP-R cells and parent Huh7 cells are respectively extracted, WB detects and compares the expression level of the hTERT protein, and the mitochondrial hTERT of drug-resistant cells is found to be obviously increased, as shown in figure 3.
The brief steps for mitochondrial protein extraction are as follows:
(1) collecting cell suspension, using Lysis Buffer containing protease inhibitor to crack, and centrifuging to remove supernatant (mainly cytoplasmic protein); (2) the cell mass is resuspended in a precipitation Buffer containing protease inhibitor for lysis, and 1000g of the cell mass is centrifuged to take the supernatant; centrifuging 6000g of the supernatant, and leaving precipitate as mitochondria; (3) adding Mitochondria Purification Buffer for resuspension; preparing a mixed solution of Mitochondria Purification Buffer and precipitation Buffer, adding a mitochondrial suspension on the surface, centrifuging, removing a supernatant, and sucking a mitochondrial precipitate to a new centrifuge tube; (4) adding Mitochondria Storage Buffer, centrifuging and removing supernatant; repeating the step (4) until the bottom of the centrifugal tube is precipitated, adding RIPA lysate, and storing at-80 ℃.
1.2Co-IP detection of the interaction of hTERT with mitochondrial protein ND1
Overexpression of hTERT in HCC cells Huh7DNConstruction of stably transfected cell Huh7 hTERTDN. Firstly, Immunoprecipitation (IP) is carried out by using an hTERT antibody, and then mass spectrum sample sending detection is carried out to screen and obtain a subunit ND1 of a molecular respiratory chain Complex complete I which is possibly combined with hTERT in mitochondrial protein. Then, an HA-ND1 expression vector fused with an HA tag is constructed, and is further verified by Co-IP: in Huh7-hTERTDNOver-expressing HA-ND1 in cells, performing positive and negative validation by performing western immunoblotting (WB) for detecting HA after Immunoprecipitation (IP) by using hTERT and performing WB for detecting hTERT after immunoprecipitation by using HA. The results are shown in FIG. 4, indicating that there is a protein interaction between hTERT and ND 1.
1.3 confocal laser verification of the interaction of hTERT with ND1
Respectively in Huh7 hTERTDNCells and Huh7 hTERTNUCIn the cells, HA-ND1 was overexpressed. hTERT is marked by green fluorescence, HA-ND1 is marked by red fluorescence, and cell nucleus is marked by blue fluorescence DAPI. Immunofluorescence detection shows that the hTERT and the HA-ND1 have interaction, and the hTERT and the HA-ND1 are overlapped to be yellow, such as the hTERT in the figure 5DNThe row Merge column. For hTERTNUCThe cells, due to mutation of mitochondrial localization sequence of hTERT, are unable to enter mitochondria, as hTERT in figure 5NUCLine Merge column shows hTERTNUCLittle overlap with the fluorescence of HA-ND1, indicating that no dichotomy was detectedWhich interact with each other.
1.4 biological Structure of ND1
Relevant data of ND1 protein is searched in UniProt database, and the structure and key amino acid sequence are arranged, and the schematic diagram is shown in FIG. 6. ND1 is 8 transmembrane protein located in the inner membrane of mitochondria, and the main functional region is 4 AA sequences (22-68, 120-146, 191-231, 273-294).
1.5 bioinformatics analysis predicts the potential interaction region of hTERT with ND1
Figure 7 shows part of the amino acid sequence of ND1 from various species. ND1 is well conserved across multiple species, suggesting an importance of its function. Through alignment analysis of ND1 sequences of different species, the interaction possibility of FMAEY (SEQ ID NO:1) and hTERT at the 224-228 amino acid sequence of human ND1 is the largest according to the prediction of the biological combination structure.
Example 2
Design and synthesis of cell-penetrating peptide
2.1 design of cell-penetrating peptides
Based on the bioinformatics prediction binding structure biological analysis, the peptide containing the FMAEY sequence has the potential to antagonize the interaction of hTERT and ND1 protein. In this example, short peptide GPFALFFMAEYT (SEQ ID NO:2) was designed against the interaction sequence of hTERT with ND 1. In order to facilitate the entry of the short peptide into cells, the N-terminal of the short peptide is further considered to be coupled with a TAT transmembrane sequence YGRKKRRQRRR (SEQ ID NO:3) to obtain a transmembrane peptide TAT-peptide, TAT-Pep for short, and the whole amino acid sequence of the transmembrane peptide is YGRKKRRQRRRGPFALFFMAEYT (SEQ ID NO: 4). The cell-penetrating peptide TAT-Pep comprises 23 amino acid residues and has a molecular weight of 2935.43.
2.2 Synthesis of cell-penetrating peptides
TAT-Pep is synthesized by the national Biotech limited of Nanjing Jinsrui of Jiangsu by a solid phase synthesis method, and the purity is more than 95 percent.
Example 3
Functional verification of cell-penetrating peptide
3.1 mechanism of action verification of cell-penetrating peptides
In Huh7 hTERTDNIn the cells, HA-ND1 was overexpressed. The group without TAT-Pep is used as a control group, and the experimental group is added with TAT-Pep, then performing a Co-IP experiment. As shown in FIG. 8, TAT-Pep significantly decreased the protein interaction of hTERT with ND1 in tumor cells, compared to the control group. The TAT-Pep can inhibit the protein interaction of hTERT and ND 1.
3.2 Effect of cell-penetrating peptides on tumor cell metabolism
In Huh7 hTERTDNIn the cells, TAT-Pep is not added as a control group, TAT-Pep is added in an experimental group, and an ATP level of the tumor cells is detected by adopting an ATP detection kit. The results are shown in fig. 9, TAT-Pep can significantly increase ATP levels of tumor cells, suggesting that TAT-Pep can enhance mitochondrial oxidative phosphorylation of tumor cells (. about.. about.p.)<0.01)。
3.3 Effect of cell-penetrating peptides on drug sensitivity of drug-resistant cells
Under the action of chemotherapeutic medicine CDDP, hTERT in tumor cells can be translocated to mitochondria, so that hTERT can inhibit oxidative phosphorylation of mitochondria after entering the mitochondria, and the survival of tumor cells and chemotherapy resistance are promoted. After demonstrating that TAT-Pep can inhibit the interaction of hTERT and ND1 protein and improve the level of mitochondrial oxidative phosphorylation, the chemotherapy sensitivity of TAT-Pep to drug-resistant Huh7 CDDP-R cells is further researched.
In Huh7 CDDP-R cells, TAT-Pep was used in combination with CDDP in the experimental group, CDDP alone was used in the control group, and CCK-8 assay was used to examine cell viability. The results show that: the half maximal inhibitory concentration (IC50) of the experimental group cells was significantly reduced compared to the control group (. p <0.01), as shown in fig. 10. The results show that TAT-Pep can significantly reduce the activity of tumor cells after CDDP treatment and reduce half inhibitory concentration (IC50), namely TAT-Pep enhances the sensitivity of Huh7 CDDP-R cells to CDDP and partially reverses drug resistance.
Has the advantages that: the invention discloses a protein interaction mechanism of hTERT and mitochondria ND1, designs and synthesizes a cell-penetrating peptide as an hTERT target, and the target can inhibit the interaction of hTERT and mitochondria ND1 protein. The invention shows that the hTERT translocated to the mitochondria of the tumor cells is interfered by the hTERT target, the interaction between the hTERT and ND1 is inhibited, the decrease of the mitochondria function of the drug-resistant tumor cells is improved, the mitochondria function is partially recovered, the sensitivity of the drug-resistant tumor cells to chemotherapeutic drugs is enhanced, and the drug resistance of the tumor cells is partially reversed.
In the embodiment, a specific mechanism of hTERT mitochondrial translocation resisting cis-platinum (CDDP) is analyzed by using only a hepatocyte liver cancer (HCC) cell model, and the effect of TAT-Pep is verified. However, the above mechanism is present in various CDDP-resistant tumor cells, for example, CDDP-resistant tumor cells of colorectal cancer, gastric cancer, and lung cancer. Therefore, the cell-penetrating peptide TAT-Pep has potential application as a sensitization regulator of CDDP (or other platinum) chemotherapeutic drugs and is used for improving the treatment effect of the CDDP (or other platinum) chemotherapeutic drugs on tumors, particularly drug-resistant tumor diseases.
Finally, it should be noted that the above-mentioned description is only a preferred embodiment of the present invention, and those skilled in the art can make various similar representations without departing from the spirit and scope of the present invention.
Claims (12)
1. An hTERT target characterized in that it has antagonistic effect on the protein interaction of hTERT with subunit MT-ND1 (abbreviated as ND1) of mitochondrial respiratory chain complex I (complex I), said target being a peptide comprising amino acid sequence FMAEY (SEQ ID NO: 1).
2. The target according to claim 1, characterized by comprising the amino acid sequence GPFALFFMAEYT (SEQ ID NO: 2).
3. The target according to claim 1 or 2, further comprising a transmembrane sequence.
4. The target according to claim 3, wherein the transmembrane sequence is YGRKKRRQRRR (SEQ ID NO: 3).
5. The target according to claim 3, characterized in that its amino acid sequence is YGRKKRRQRRRGPFALFFMAEYT (SEQ ID NO: 4).
6. The method for synthesizing the target substance according to any one of claims 1 to 5, wherein the target substance is synthesized by a polypeptide solid phase synthesis method.
7. Use of a human telomerase reverse transcriptase (hTERT) target in the preparation of a modulator that antagonizes hTERT/ND1 protein interaction.
8. The use according to claim 7, characterized in that said hTERT is mitochondrially localized hTERT in tumor cells.
9. The use of claim 8, wherein said tumor cell is resistant to a chemotherapeutic agent and said modulator has the effect of increasing the sensitivity of said tumor cell to said chemotherapeutic agent.
10. The use according to claim 9, wherein said modulator increases the sensitivity of said tumor cell to said chemotherapeutic agent by increasing mitochondrial oxidative phosphorylation.
11. Use according to claim 9 or 10, characterized in that the chemotherapeutic agent is Cisplatin (CDDP) or other platinum group drugs.
12. A modulator characterized by comprising the target of any one of claims 1 to 5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105582525A (en) * | 2014-10-24 | 2016-05-18 | 佛山市龙杰生物科技有限公司 | Application of CIRP (cold-inducible RNA binding protein) in preparing telomerase binding agent or telomerase activity regulating agent |
| WO2017177178A1 (en) * | 2016-04-07 | 2017-10-12 | Case Western Reserve University | Tdp-43 mitochondrial localization inhibitor for the treatment of neurodegenerative disease |
| CN109666064A (en) * | 2018-12-29 | 2019-04-23 | 上海锐赛生物技术有限公司 | SALL4-RBBp4 complex blocks polypeptide and derivative antineoplastic polypeptide and its application |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105582525A (en) * | 2014-10-24 | 2016-05-18 | 佛山市龙杰生物科技有限公司 | Application of CIRP (cold-inducible RNA binding protein) in preparing telomerase binding agent or telomerase activity regulating agent |
| WO2017177178A1 (en) * | 2016-04-07 | 2017-10-12 | Case Western Reserve University | Tdp-43 mitochondrial localization inhibitor for the treatment of neurodegenerative disease |
| CN109666064A (en) * | 2018-12-29 | 2019-04-23 | 上海锐赛生物技术有限公司 | SALL4-RBBp4 complex blocks polypeptide and derivative antineoplastic polypeptide and its application |
Non-Patent Citations (2)
| Title |
|---|
| NATALIA LIPINSKA等: "Telomerase and drug resistance in cancer", 《CELL MOL LIFE SCI》 * |
| 杨金亮等: "抑制端粒酶活性能增加胃癌细胞对顺铂的敏感性", 《中华内科杂志》 * |
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