KR101755613B1 - A method for screening of substances for treating gastric cancer using activities of neurotensin receptor - Google Patents
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Abstract
One aspect includes the steps of incubating a gastric cancer cell and a candidate substance; Measuring the level of phosphorylation of one or more proteins present on the signal transduction pathway of neurotensin receptors in said cells; And determining the substance as a substance for treating gastric cancer when the phosphorylation level of the protein is lower than that of a control cell.
Description
The present invention relates to a method for screening a substance for treating gastric cancer using the activity of neurotensin receptors.
Gastric cancer is the second most common cancer worldwide. Especially, our country has the highest incidence of gastric cancer in the world because of eating habit of eating salty and spicy foods. In the development of gastric cancer treatment, cost and time loss are significant when development is stopped at the clinical trial stage, so verifying the usefulness of new drug candidates at the screening stage of new drugs is the best way to prevent waste of time and cost.
In general, screening of new drug candidates prior to clinical trials and pre-clinical trials will analyze the ability of the candidate drug candidate to inhibit the target substance. However, the analysis of the inhibitory ability of a candidate drug substance against a target substance does not provide information on toxicity or side effects that are the main reason for exclusion from preclinical or clinical trials.
In addition to the target substance, a new method for analyzing the effect of a candidate substance on other proteins involved in the formation of cancer cells is required to more accurately determine the usefulness of a candidate substance in the screening of a new drug.
One aspect provides a method of screening for a substance for treating gastric cancer that utilizes the activity of neurotensin receptors.
One aspect includes the steps of incubating a gastric cancer cell and a candidate substance; Measuring the level of phosphorylation of one or more proteins present on the signal transduction pathway of a neurotensin receptor in the cell; And determining the substance as a substance for treating gastric cancer when the phosphorylation level of the protein is lower than that of a control cell.
Incubation of the gastric cancer cells with the candidate substance may be performed in the presence of neurotensin. In this case, the control cells may be normal cells or the same kind of gastric cancer cells incubated with neurotensin.
The candidate substance may be a substance known in the art as a neurotensin receptor antagonist or an epidermal growth factor receptor antagonist. In addition, the candidate substance may be a substance anticipated or considered as an antagonist for neurotensin receptors or an epithelial growth factor receptor antagonist. Neurotensin receptors are transmembrane receptors that bind neurotensin, a neurotransmitter, and may include neurotensin receptor 1 (NTSR1) and neurotensin receptor 2 (NTSR2). Epithelial growth factor receptor may refer to a cell surface receptor for a member of the epithelial growth factor family of extracellular protein ligands.
The substance may have an IC 50 for neurotensin receptors from 2 nM to 0.2 μM, from 5 nM to 0.15 μM, from 10 nM to 0.1 μM, or from 20 nM to 50 nM. The material may have an IC 50 for the epithelial growth factor receptor from 8 nM to 0.4 uM, 10 nM to 0.2 uM, 20 nM to 0.1 uM, or 40 nM to 80 nM.
The one or more proteins may belong to the protein kinase C pathway, the MAP kinase pathway, and / or the PI3K / AKT / mTOR pathway. The at least one protein may be at least one selected from the group consisting of PKC, Raf, MAPK, ERK, Ras, PI3K, Akt, mTOR, FAK and STAT3.
Measurement of the phosphorylation level can be measured by immunofluorescence, enzyme immunoassay, Western blotting, RT-PCR, capillary electrophoresis-mass spectrometry, spectrophotometer, or a combination thereof.
The gastric cancer cell may be a gastric cancer cell strain commonly used in the art. The gastric cancer cells may be human or mouse-derived. The gastric cancer cell may be an intestinal type gastric cancer cell or a diffuse type gastric cancer cell. For example, the gastric cancer cells may be MKN-1, MKN-45, MKN-74, SNU-1, SNU-5, SNU-16 or AGS.
The method may further comprise measuring the level of expression or activity of matrix metalloproteinase 9 (MMP-9) in the cells. MMP-9 is a class of enzymes belonging to zinc-metalloproteinases involved in the degradation of extracellular matrix, and may also be named gelatinase B or type IV collagenase.
The expression or activity level of MMP-9 may be measured by Western blotting, immunoassay, capillary electrophoresis-mass spectrometry, liquid chromatography-mass spectrometry, spectrophotometer, or a combination thereof. The activity level of MMP-9 may be measured from a signal generated from a reaction product of the cell and a substrate of MMP-9.
The method may further comprise measuring the mobility or cell membrane permeability of the cell. The cell mobility or cell membrane permeability can be measured by a cell invasion assay or a cell migration assay. The cellular mobility or cell membrane permeability can be considered together with the expression or activity level of MMP-9 in the cell.
The method for screening a substance for treating gastric cancer according to one aspect can be used to evaluate the ability of a candidate drug candidate to inhibit neurotensin receptor activity. In addition, the adverse effects of candidate substances can be predicted early by analyzing the effect of the candidate drug substance on the neurotensin receptor signaling pathway.
Figure 1 shows that NT and EGF bind to receptors of neurotensin (NT) and epithelial growth factor (EGF), respectively, and phosphorylation signal is transmitted through protein kinase C pathway, MAP kinase pathway, or PI3K / AKT / mTOR pathway, -9 < / RTI > increases and cancer metastasis occurs.
FIG. 2A is a quantitative standard curve of NT, and FIG. 2B is a quantitative analysis result of NT of HFE-145 normal cells and MKN-1 and MKN-45 cells of stomach cancer cells.
FIGS. 3A to 3F show the results of measuring the expression level and activity of MMP-9 in blood samples of stomach cancer cells and stomach cancer patients treated with NT or NT and NT receptor inhibitors.
4A to 4C are results of analysis of the phosphorylation level of proteins present on MAPK and mTOR signaling pathways after treatment of NT with MKN-1. 4A and 4B show quantitative analysis results by Western blotting and densitometer confirming the phosphorylation level of PKC, c-raf, and ERK in the MAPK pathway, respectively. Figure 4c shows the results of analysis of PI3K and Akt phosphorylation levels of the mTOR pathway.
FIGS. 5A and 5B show the results of analysis of the phosphorylation levels of proteins present on the MAPK signal transduction pathway after treatment of NT with MKN-45. Western blotting and PKC, c-raf and ERK, The result of quantitative analysis by densitometer is shown.
6A and 6B are graphs showing the phosphorylation levels of proteins present on the MAPK signaling pathway after treatment of NT or NT and NT receptor inhibitors with HFE-145 and MKN-1 cells, respectively, and PKC, c-raf, And Western blotting confirmed the phosphorylation level of ERK and quantitative analysis results using a densitometer.
7a and 7b are graphs showing the phosphorylation levels of proteins present on the MAPK signaling pathway after treatment with NT or NT and NT receptor inhibitors on HFE-145 and MKN-45 cells, respectively. These results indicate that PKC, c-raf, And Western blotting confirmed the phosphorylation level of ERK and quantitative analysis results using a densitometer.
FIGS. 8A and 8B are the results of measurement of the mobility of HFE-145 and MKN-1 cells, respectively. As a result, the numbers of cells migrated in the scratched plates after 24 hours of treatment with NT or NT and NT receptor inhibitors, respectively, Results are shown.
FIGS. 9A and 9B show cell permeability of HFE-145 and MKN-1 cells, respectively. As a result, the number of cells permeating the matrigel after 24 hours of treatment with NT or NT and NT receptor inhibitor, And the results of quantitative analysis are shown.
FIG. 10A shows the results of comparing the activity of MMP-9 with the control group after NT treatment of lung cancer cells. FIG. 10B shows the results of comparing the MMP-9 activity with the control group after treating NT with breast cancer cells.
11 is a procedure for evaluating the usefulness of candidate substances for the treatment of gastric cancer through evaluation of neurotensin receptor inhibitor of the present invention, MMP-2, MMP-9 activity measurement, cell mobility test, and cell metastasis test.
Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
Example One: MMP -9 activity analysis
1.1. Blood sample preparation and ELISA analysis
500 μl of normal human blood samples and blood samples from patients with gastric cancer obtained from Catholic Medical School were diluted 2-fold with 10% formic acid buffer and then extracted with 1 cc of Oasis HLB (30 mg) Extraction Cartridge Solid Phase Extraction Kit (Waters, Ireland) Respectively. In addition, serum and plasma endogenous peptides were isolated from proteins using a 30 kDa molecular cut-off filter (Millipore, USA). The solution containing the extracted peptides was dried using N 2 Evaporator and Freeze-Dryer, and then dissolved in 50 μl of assay buffer provided by each manufacturer of the ELISA kit for immunological analysis.
1.2. Cell line preparation and cell culture
MKN-1 and MKN-45, human lung cancer cell line A549, and breast cancer cell line MDA-MB321 were purchased from Korean Cell Line Bank. The HFE-145 cell line was purchased from a cell line cultured in the laboratory of Professor Park Won-sang of Catholic University.
50,000 cells / cm 2 were cultured on a 60 mm dish plate (Corning Life Sciences, Acton, MA) for the MKN-1 cell line, and 25,000 cells / cm 2 were cultured for the MKN-45 cell line. After 24 hours of incubation, the cells were replaced with serum-free medium and cultured for another 24 hours. After that, neurotensin was added to measure the amount of protein expressed on the phosphorylated signal transduction pathway and the activity of MMP-9. For the A549 and MDA-MB321 cell lines, 40,000 cells / cm 2 were cultured for 24 hours and then MMP-9 activity was measured.
1.3. MMP -9 Activity measurement
Neurotensin or MKN-1, MKN-45, HFE-145, A549, and MDA-MB321 cell lines treated with DMSO alone were incubated for 6 hours, washed with phosphate buffered saline (PBS) And incubated with 7-methoxycoumarine-4-acetylPro-Leu-Gly-Leu- (2,4-dinitrophenylamino) -Ala-Arg amide and adjuvant APMA (p-amino mercuric acid). The intensity of fluorescence increased when the substrate was cleaved by MMP-9 was measured by fluorescence spectrophotometer (λexc = 328 nm, λemi = 393 nm).
FIGS. 3A to 3F show the results of measuring the expression level and activity of MMP-9 in blood samples of stomach cancer cells and stomach cancer patients treated with NT or NT and NT receptor inhibitors.
FIGS. 3A and 3B show the results of comparing the expression levels of MMP-9 in HFE-145 and MKN-1, HFE-145 and MKN-45, , HFE-145, and MKN-45. Thus, it was confirmed that the expression amount and activity of MMP-9 increased by NT treatment in stomach cancer cells decreased to a level close to that of normal cells by NT receptor inhibitor treatment.
FIG. 3E shows the results of comparing the activities of MMP-9 in blood samples (DGC) of blood samples (IGC) and diffuse-type gastric cancer patients of patients with intestinal type gastric cancer, FIG. And the activity of MMP-9 in MKN-1 and diffuse gastric cancer cell line MKN-45.
Example 2: NT Analysis of phosphorylation level of receptor signaling pathway protein
2.1. Protein extraction and Western Blotting
MKN-1, MKN-45, HFE-145, A549, and MDA-MB321 cell lines were separated from the plates using trypsin-EDTA (TE) and washed twice with PBS. Cells were lysed with TNN-EDTA lysis buffer (50 mM Tris (pH 7.4), 150 mM NaCl, 0.5% NP40 (Nonidet P-40), 1 mM EDTA, 200 mM Na 3 VO 4 ) The supernatant was separated by centrifugation. Protein was quantified with bicinchoninic acid kit (Pierce) and the same amount of protein was separated by SDS-PAGE using 10% polyacrylamide minigel. Proteins were transferred to a nitrocellulose membrane (Pall Corporation) and blocked with PBS complex solution (containing 0.2
(1: 1000), total PKC (1: 1000), phospho-Erk1 / 2 (1: 1000), total Erk1 / 2 , phospho-Akt (1: 1000), total Akt (1: 1000), phospho-c-Raf (1: 1000), total c-Raf After incubation with PI3 Kinase (1: 1000) and anti-β-actin (1: 5000), protein bands were quantified using horseradish peroxidase-labeled secondary antibody (HRP-labeled Ab). Luminal reagent (Santa Cruz Biotechnology, Inc., CA, USA) was used as a fluorescent substrate.
2.2. Phosphorylation level analysis
Phosphorylation levels of each protein present on protein kinase C pathway, MAP kinase pathway, or PI3K / AKT / mTOR pathway in gastric cancer cells MKN-1 and MKN-45 were measured by the method described in 2.1.
4A to 4C are results of analysis of the phosphorylation level of proteins present on MAPK and mTOR signaling pathways after treatment of NT with MKN-1. Figures 4a and 4b show quantitative analysis by western blotting and densitometry confirming the phosphorylation levels of PKC, c-raf, and ERK, respectively, in the MAPK pathway. Figure 4c shows the results of analysis of PI3K and Akt phosphorylation levels of the mTOR pathway. As shown in FIGS. 4A to 4C, phosphorylation signals of PKC, c-raf, ERK and PI3K began to increase and declined after 10 minutes after NT treatment of MKN-1 cells. In the case of Akt, the phosphorylated signal increased 10 minutes after NT treatment. Through this, we confirmed the signal transduction pathway and degree of phosphorylation by NT stimulation of intestinal cancer cells.
FIGS. 5A and 5B show the results of analysis of the phosphorylation levels of proteins present on the MAPK signal transduction pathway after treatment of NT with MKN-45. Western blotting and PKC, c-raf and ERK, The result of quantitative analysis by densitometer is shown. As shown in FIGS. 5A and 5B, phosphorylation signals in PKC and c-raf began to increase after 5 minutes of treatment with NT on MKN-45 cells and decreased after 10 minutes. In the case of ERK, phosphorylation signal increased 10 min after treatment with NT and decreased after 20 min. Through this, we confirmed the signaling pathway and degree of phosphorylation by NT stimulation of diffuse stomach cancer cells.
6A and 6B are graphs showing the phosphorylation levels of proteins present on the MAPK signaling pathway after treatment of NT or NT and NT receptor inhibitors with HFE-145 and MKN-1 cells, respectively, and PKC, c-raf, And Western blotting confirmed the phosphorylation level of ERK and quantitative analysis results using a densitometer. As shown in FIGS. 6A and 6B, there is no difference in the phosphorylation level in HFE-145, which is a normal cell. However, NT treatment of MKN-1 cells increases phosphorylation level and treatment of NT and NT receptor inhibitor (Cont), which was not treated with NT. This confirms that the NT receptor inhibitor inhibits protein phosphorylation on NT signaling pathway in intestinal cancer cells.
7a and 7b are graphs showing the phosphorylation levels of proteins present on the MAPK signaling pathway after treatment with NT or NT and NT receptor inhibitors on HFE-145 and MKN-45 cells, respectively. These results indicate that PKC, c-raf, And Western blotting confirmed the phosphorylation level of ERK and quantitative analysis results using a densitometer. As shown in FIGS. 7A and 7B, there is no difference in the phosphorylation level in normal cells, but when NT is treated with MKN-45 cells, the phosphorylation level is increased and when NT and NT receptor inhibitor are treated together, But not in the control group. This confirms that the NT receptor inhibitor inhibits protein phosphorylation on the NT signaling pathway in diffuse gastric cancer cells.
Example 3: Cell Mobility and Permeability Analysis
3.1. Wound healing analysis wound - healing assay )
Cells were cultured in 6-well plates and scraped off cells in a constant direction with a sterile pipette tip. The cells were incubated in serum-free medium for 24 hours, and the medium was replaced with 5% FBS containing NT and SR48692 for 24 hours.
FIGS. 8A and 8B are the results of measurement of the mobility of HFE-145 and MKN-1 cells, respectively. As a result, microscopic photographs and quantitative analysis of the numbers of cells migrated from scratched plates after 24 hours of NT or NT and SR48692 treatment, respectively . As shown in FIGS. 8A and 8B, when NT was treated with MKN-1 cells, cell mobility increased and when NT and NT receptor inhibitors were treated together, cell mobility decreased. This confirms that the mobility of stomach cancer cells increased by NT is reduced above normal cell levels by treatment with NT receptor inhibitors.
3.2. Matrigel Penetration analysis ( matrigel invasion assay )
Transmembrane permeability was examined using trans-well chambers (8 μm pore size). 1 × 10 5 cells / well were placed in a stomach chamber coated with Matrigel (BD Bioscience, CA, USA) with 100 μl of serum-free RPMI-1640 and incubated for 24 hours. Cells infiltrated into the lower chamber were fixed with 10% formaldehyde, stained with Gimsa for 10 minutes, and observed with a fluorescence microscope to measure and quantitate the number of cells. All experiments were repeated three times. Statistical analysis was performed using Sigma Plot software version 8.0 from Systat Software Inc. (San Jose, CA, USA) and MedCalc software (Ostend Belgium) were used, and t-test and linear regression analysis were performed. Statistical significance was judged to be significant when the calculated P value was less than 0.05.
FIGS. 9A and 9B show cell permeability of HFE-145 and MKN-1 cells, respectively. As a result, the number of cells permeating the matrigel after 24 hours of treatment with NT or NT and NT receptor inhibitor, And the results of quantitative analysis are shown. As shown in FIGS. 9A and 9B, when NT was treated with MKN-1 cells, cell membrane permeability increased and cell permeability decreased when NT and NT receptor inhibitors were treated together. This confirms that the cell membrane permeability of gastric cancer cells increased by NT was reduced above the normal cell level by NT receptor inhibitor treatment.
Claims (10)
Measuring the level of phosphorylation of one or more proteins present on the signal transduction pathway of a neurotensin receptor in the cell;
Measuring the expression or activity level of matrix metalloproteinase 9 (MMP-9) in said cells; And
Determining the substance as a substance for the treatment of gastric cancer when the phosphorylation level of the protein is lower than that of the control cells or the expression or activity level of MMP-9 is increased as compared to the control cells.
A method for screening substances for treating gastric cancer.
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| KR101284014B1 (en) | 2010-11-24 | 2013-07-09 | (주)지노믹트리 | Methylation Biomarker of Gastric Cancer Specific for Gastric Cancer Diagnosis |
| KR101438530B1 (en) | 2012-05-29 | 2014-09-12 | 한국과학기술연구원 | Biomarker composition for diagnosing stomach cancer and method for diagnosis using the same |
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| KR101284014B1 (en) | 2010-11-24 | 2013-07-09 | (주)지노믹트리 | Methylation Biomarker of Gastric Cancer Specific for Gastric Cancer Diagnosis |
| KR101438530B1 (en) | 2012-05-29 | 2014-09-12 | 한국과학기술연구원 | Biomarker composition for diagnosing stomach cancer and method for diagnosis using the same |
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| Title |
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| CANCER (1997), vol.79(9), 1787-1793 |
| Cancer Res (2006), vol.66(12), 6243-6249. |
| CANCER RESEARCH (2003), vol.63, 2379-2387. |
| Int. J. Cancer (1999), vol.80, 448-454. |
| Peptides 22 (2001), 109-115. |
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