title: PUMA mediates the combinational therapy of 5-FU and NVP-BEZ235 in colon cancer.
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.
authors.affiliation: The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.|Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, China.|Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Huanan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, China.|Department of Biology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Shimin
authors.initials: S
authors.lastname: Pei
authors.affiliation: The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Molecular Medicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
authors.forename: Degui
authors.initials: D
authors.lastname: Lin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil
keywords: Akt; NVP-BEZ235; PUMA; colon cancer; p53