The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin
Background: Chemoresistance is a common event after cancer chemotherapy, including gastric cancer (GC). Cisplatin has been reported to induce the DNA damage response (DDR), thus leading to chemoresistance. VE-821, a specific inhibitor of ATR, has been proven to suppress a variety of solid malignanci...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-10-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523323001298 |
| _version_ | 1797745975740071936 |
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| author | Haochen Su Yue Yuan Jiatong Tang Yixuan Zhang Hao Wu Yin Zhang Jiawei Liang Lei Wang Xiaoping Zou Shuling Huang Shu Zhang Ying Lv |
| author_facet | Haochen Su Yue Yuan Jiatong Tang Yixuan Zhang Hao Wu Yin Zhang Jiawei Liang Lei Wang Xiaoping Zou Shuling Huang Shu Zhang Ying Lv |
| author_sort | Haochen Su |
| collection | DOAJ |
| description | Background: Chemoresistance is a common event after cancer chemotherapy, including gastric cancer (GC). Cisplatin has been reported to induce the DNA damage response (DDR), thus leading to chemoresistance. VE-821, a specific inhibitor of ATR, has been proven to suppress a variety of solid malignancies effectively. Our study aimed to explore the effect of VE-821 on enhancing the chemical sensitivity to cisplatin and clarify the potential molecular mechanisms. Methods: Cell viability and apoptosis of MKN-45 and AGS were measured by CCK8 and flow cytometry assay respectively. Western blotting was used to detect the expression of target proteins. TCGA database was used to analyze the correlation between the ATR expression with the prognosis of GC patients. The viability of GC organoids was detected by Cell Titer Glo (CTG) through luminescence. Results: Cisplatin inhibited the proliferation and induced apoptosis of GC cells with a relatively high IC50 value, and increased the phosphorylation levels of ATR-CHK1 and H2AX. VE-821 achieved the same effects but by downregulating the phosphorylation levels of the ATR-CHK1 pathway. Besides, higher ATR expression in GC tissues was positively correlated with higher pathological stage in GC patients. Interestingly, ATR inhibition reversed cisplatin-induced STAT3 activation and enhanced H2AX levels. Moreover, VE-821 significantly sensitized GC cells to cisplatin, and these two drugs had synergistic effects in GC cell lines, organoids, and in vivo. Conclusion: Our results suggested VE-821 sensitized GC cells to cisplatin via reversing DDR activation. And VE-821 treatment may be a promising therapeutic strategy for GC patients with cisplatin resistance. |
| first_indexed | 2024-03-12T15:31:27Z |
| format | Article |
| id | doaj.art-6b10b43d005d44b9bf26cd246174cbc7 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-03-12T15:31:27Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-6b10b43d005d44b9bf26cd246174cbc72023-08-10T04:34:07ZengElsevierTranslational Oncology1936-52332023-10-0136101743The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatinHaochen Su0Yue Yuan1Jiatong Tang2Yixuan Zhang3Hao Wu4Yin Zhang5Jiawei Liang6Lei Wang7Xiaoping Zou8Shuling Huang9Shu Zhang10Ying Lv11Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR China; Institute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, The Third People's Hospital of Yancheng, Yancheng, Jiangsu 224000, PR ChinaState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210008, PR ChinaInstitute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR ChinaInstitute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR ChinaInstitute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR ChinaInstitute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR ChinaInstitute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR ChinaInstitute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR ChinaInstitute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR China; Institute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR China; Corresponding authors at: Institute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China.Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR China; Institute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, PR China; Corresponding authors at: Institute of Pancreatology, Nanjing University, Nanjing, Jiangsu 210008, PR China.Background: Chemoresistance is a common event after cancer chemotherapy, including gastric cancer (GC). Cisplatin has been reported to induce the DNA damage response (DDR), thus leading to chemoresistance. VE-821, a specific inhibitor of ATR, has been proven to suppress a variety of solid malignancies effectively. Our study aimed to explore the effect of VE-821 on enhancing the chemical sensitivity to cisplatin and clarify the potential molecular mechanisms. Methods: Cell viability and apoptosis of MKN-45 and AGS were measured by CCK8 and flow cytometry assay respectively. Western blotting was used to detect the expression of target proteins. TCGA database was used to analyze the correlation between the ATR expression with the prognosis of GC patients. The viability of GC organoids was detected by Cell Titer Glo (CTG) through luminescence. Results: Cisplatin inhibited the proliferation and induced apoptosis of GC cells with a relatively high IC50 value, and increased the phosphorylation levels of ATR-CHK1 and H2AX. VE-821 achieved the same effects but by downregulating the phosphorylation levels of the ATR-CHK1 pathway. Besides, higher ATR expression in GC tissues was positively correlated with higher pathological stage in GC patients. Interestingly, ATR inhibition reversed cisplatin-induced STAT3 activation and enhanced H2AX levels. Moreover, VE-821 significantly sensitized GC cells to cisplatin, and these two drugs had synergistic effects in GC cell lines, organoids, and in vivo. Conclusion: Our results suggested VE-821 sensitized GC cells to cisplatin via reversing DDR activation. And VE-821 treatment may be a promising therapeutic strategy for GC patients with cisplatin resistance.http://www.sciencedirect.com/science/article/pii/S1936523323001298ATR inhibitorCisplatinGastric cancerChemoresistanceOrganoid |
| spellingShingle | Haochen Su Yue Yuan Jiatong Tang Yixuan Zhang Hao Wu Yin Zhang Jiawei Liang Lei Wang Xiaoping Zou Shuling Huang Shu Zhang Ying Lv The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin Translational Oncology ATR inhibitor Cisplatin Gastric cancer Chemoresistance Organoid |
| title | The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin |
| title_full | The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin |
| title_fullStr | The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin |
| title_full_unstemmed | The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin |
| title_short | The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin |
| title_sort | atr inhibitor ve 821 increases the sensitivity of gastric cancer cells to cisplatin |
| topic | ATR inhibitor Cisplatin Gastric cancer Chemoresistance Organoid |
| url | http://www.sciencedirect.com/science/article/pii/S1936523323001298 |
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