PUMA mediates the combinational therapy of 5-FU and NVP-BEZ235 in colon cancer
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Huanan Wang1,2,4,*, Lingling Zhang2,3,*, Xu Yang1,*, Yipeng Jin1,*, Shimin Pei1, Di Zhang1, Hong Zhang1, Bin Zhou1, Yingjie Zhang2,**, Degui Lin1,**
1The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
2Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, China
3Department of Biology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
4Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
*These authors have contributed equally as first authors
**These authors have contributed equally as last authors
Yingjie Zhang, e-mail: [email protected]
Degui Lin, e-mail: [email protected]
Keywords: colon cancer, NVP-BEZ235, PUMA, Akt, p53
Received: November 14, 2014 Accepted: April 20, 2015 Published: May 02, 2015
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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