Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells
Abstract Background Gemcitabine is the standard first-line chemotherapy regimen for pancreatic cancer. However, its therapeutic value is substantially limited in pancreatic cancer patients due to occurrence of resistance towards gemcitabine. A strategy of combined chemo-regimens is widely employed i...
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| Format: | Article |
| Language: | English |
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BMC
2019-06-01
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| Series: | Cell & Bioscience |
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| Online Access: | http://link.springer.com/article/10.1186/s13578-019-0312-0 |
| _version_ | 1818306352140779520 |
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| author | Hehe Li Zhengle Zhang Chenggang Gao Shihong Wu Qingke Duan Heshui Wu Chunyou Wang Qiang Shen Tao Yin |
| author_facet | Hehe Li Zhengle Zhang Chenggang Gao Shihong Wu Qingke Duan Heshui Wu Chunyou Wang Qiang Shen Tao Yin |
| author_sort | Hehe Li |
| collection | DOAJ |
| description | Abstract Background Gemcitabine is the standard first-line chemotherapy regimen for pancreatic cancer. However, its therapeutic value is substantially limited in pancreatic cancer patients due to occurrence of resistance towards gemcitabine. A strategy of combined chemo-regimens is widely employed in clinical settings in attempt to reduce the chance of developing therapeutic resistance. Valproic acid (VPA) has been reported as a promising anticancer drug in various clinical trials and studies. However, the clinical value and potential dose–effect of VPA in combination with gemcitabine for pancreatic cancer treatment are under investigated. Results In this study, we determined the synergistic effect of VPA and gemcitabine and found that high-dose VPA significantly and dose-dependently enhanced the sensitivity of pancreatic cancer cells to gemcitabine. Intriguingly, low-dose VPA potentiated the migration and invasion of pancreatic cancer cells that already showed gemcitabine-induced motility. Moreover, low-dose VPA increased the reactive oxygen species (ROS) production, which activated AKT to further stimulate the activation of STAT3, Bmi1 expression and eventually promoted the migration and invasion of pancreatic cancer cells induced by gemcitabine. Whereas high-dose VPA stimulated excessive ROS accumulation that promoted p38 activation, which suppressed the activation of STAT3 and Bmi1. Conclusion Pancreatic cancer cells respond differentially towards low- or high-dose of VPA in combination with gemcitabine, and a low VPA further potentiate pancreatic cancer cell to migrate and invade. Our results suggest that STAT3/Bmi1 signaling cascade, which is regulated by ROS-dependent, AKT- or p38-modulated pathways, primarily mediated the sensitivity and motility of pancreatic cancer cells towards combined gemcitabine and VPA regimen. These findings suggest a highly clinically relevant new mechanism of developing resistance against combined chemo-regimens, warranting further mechanistic and translational exploration for VPA in combination with gemcitabine and other chemotherapies. |
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| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-12-13T06:41:07Z |
| publishDate | 2019-06-01 |
| publisher | BMC |
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| series | Cell & Bioscience |
| spelling | doaj.art-539fd670cb204f68a7f297f8e1fd8a5a2022-12-21T23:56:24ZengBMCCell & Bioscience2045-37012019-06-019111510.1186/s13578-019-0312-0Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cellsHehe Li0Zhengle Zhang1Chenggang Gao2Shihong Wu3Qingke Duan4Heshui Wu5Chunyou Wang6Qiang Shen7Tao Yin8Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pancreatic Surgery, Renmin Hospital, Wuhan UniversityDepartment of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer CenterDepartment of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Gemcitabine is the standard first-line chemotherapy regimen for pancreatic cancer. However, its therapeutic value is substantially limited in pancreatic cancer patients due to occurrence of resistance towards gemcitabine. A strategy of combined chemo-regimens is widely employed in clinical settings in attempt to reduce the chance of developing therapeutic resistance. Valproic acid (VPA) has been reported as a promising anticancer drug in various clinical trials and studies. However, the clinical value and potential dose–effect of VPA in combination with gemcitabine for pancreatic cancer treatment are under investigated. Results In this study, we determined the synergistic effect of VPA and gemcitabine and found that high-dose VPA significantly and dose-dependently enhanced the sensitivity of pancreatic cancer cells to gemcitabine. Intriguingly, low-dose VPA potentiated the migration and invasion of pancreatic cancer cells that already showed gemcitabine-induced motility. Moreover, low-dose VPA increased the reactive oxygen species (ROS) production, which activated AKT to further stimulate the activation of STAT3, Bmi1 expression and eventually promoted the migration and invasion of pancreatic cancer cells induced by gemcitabine. Whereas high-dose VPA stimulated excessive ROS accumulation that promoted p38 activation, which suppressed the activation of STAT3 and Bmi1. Conclusion Pancreatic cancer cells respond differentially towards low- or high-dose of VPA in combination with gemcitabine, and a low VPA further potentiate pancreatic cancer cell to migrate and invade. Our results suggest that STAT3/Bmi1 signaling cascade, which is regulated by ROS-dependent, AKT- or p38-modulated pathways, primarily mediated the sensitivity and motility of pancreatic cancer cells towards combined gemcitabine and VPA regimen. These findings suggest a highly clinically relevant new mechanism of developing resistance against combined chemo-regimens, warranting further mechanistic and translational exploration for VPA in combination with gemcitabine and other chemotherapies.http://link.springer.com/article/10.1186/s13578-019-0312-0Pancreatic cancerGemcitabineValproic acidCombined chemotherapyBmi1 |
| spellingShingle | Hehe Li Zhengle Zhang Chenggang Gao Shihong Wu Qingke Duan Heshui Wu Chunyou Wang Qiang Shen Tao Yin Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells Cell & Bioscience Pancreatic cancer Gemcitabine Valproic acid Combined chemotherapy Bmi1 |
| title | Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells |
| title_full | Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells |
| title_fullStr | Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells |
| title_full_unstemmed | Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells |
| title_short | Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells |
| title_sort | combination chemotherapy of valproic acid vpa and gemcitabine regulates stat3 bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells |
| topic | Pancreatic cancer Gemcitabine Valproic acid Combined chemotherapy Bmi1 |
| url | http://link.springer.com/article/10.1186/s13578-019-0312-0 |
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