PUMA mediates the combinational therapy of 5-FU and NVP-BEZ235 in colon cancer |
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Authors: | Huanan Wang Lingling Zhang Xu Yang Yipeng Jin Shimin Pei Di Zhang Hong Zhang Bin Zhou Yingjie Zhang Degui Lin |
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Affiliation: | 1. The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China;2. Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, China;3. Department of Biology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China;4. Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China |
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Abstract: | Colon cancer is the third most common cancer in humans which has a high mortality rate, and 5-Fluorouracil (5-FU) is one of the most widely used drugs in colon cancer therapy. However, acquired chemoresistance is becoming the major challenges for patients, and the molecular mechanism underlying the development of 5-FU resistance is still poorly understood. In this study, a newly designed therapy in combination with 5-FU and NVP-BEZ235 in colon cancer cells (HCT-116 and RKO) was established, to investigate the mechanism of 5-FU resistance and optimize drug therapy to improve outcome for patients. Our results show 5-FU induced cell apoptosis through p53/PUMA pathway, with aberrant Akt activation, which may well explain the mechanism of 5-FU resistance. NVP-BEZ235 effectively up-regulated PUMA expression, mainly through inactivation of PI3K/Akt and activation of FOXO3a, leading to cell apoptosis even in the p53−/− HCT-116 cells. Combination treatment of 5-FU and NVP-BEZ235 further increased cell apoptosis in a PUMA/Bax dependent manner. Moreover, significantly enhanced anti-tumor effects were observed in combination treatment in vivo. Together, these results demonstrated that the combination treatment of 5-FU and NVP-BEZ235 caused PUMA-dependent tumor suppression both in vitro and in vivo, which may promise a more effective strategy for colon cancer therapy. |
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Keywords: | colon cancer NVP-BEZ235 PUMA Akt p53 |
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