title: Pazopanib, a novel multi-kinase inhibitor, shows potent antitumor activity in colon cancer through PUMA-mediated apoptosis.
abstract: Colon cancer is still the third most common cancer which has a high mortality but low five-year survival rate. Novel tyrosine kinase inhibitors (TKI) such as pazopanib become effective antineoplastic agents that show promising clinical activity in a variety of carcinoma, including colon cancer. However, the precise underlying mechanism against tumor is unclear. Here, we demonstrated that pazopanib promoted colon cancer cell apoptosis through inducing PUMA expression. Pazopanib induced p53-independent PUMA activation by inhibiting PI3K/Akt signaling pathway, thereby activating Foxo3a, which subsequently bound to the promoter of PUMA to activate its transcription. After induction, PUMA activated Bax and triggered the intrinsic mitochondrial apoptosis pathway. Furthermore, administration of pazopanib highly suppressed tumor growth in a xenograft model. PUMA deletion in cells and tumors led to resistance of pazopanib, indicating PUMA-mediated pro-apoptotic and anti-tumor effects in vitro and in vivo. Combing pazopanib with some conventional or novel drugs, produced heightened and synergistic antitumor effects that were associated with potentiated PUMA induction via different pathways. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of pazopanib in colon cancer cells and provide the rationale for clinical evaluation.
authors.affiliation: College of Biology, Hunan University, Changsha, China.|Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China.|Department of Internal Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.|School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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 Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, China.|Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: College of Biology, Hunan University, Changsha, China.
authors.forename: Juchang
authors.initials: J
authors.lastname: Zhong
authors.affiliation: College of Biology, Hunan University, Changsha, China.
authors.forename: Rongcheng
authors.initials: R
authors.lastname: Yu
authors.affiliation: College of Biology, Hunan University, Changsha, China.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Huang
authors.affiliation: College of Biology, Hunan University, Changsha, China.
authors.forename: Honghui
authors.initials: H
authors.lastname: Wang
authors.affiliation: College of Biology, Hunan University, Changsha, China.
authors.forename: Zhikai
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Department of Internal Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Biology, Hunan University, Changsha, China.|Shenzhen Institute, Hunan University, Shenzhen, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007191:Indazoles; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071316:Forkhead Box Protein O3; D007191:Indazoles; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C438378:BBC3 protein, human; C499517:FOXO3 protein, human; C516667:pazopanib
keywords: Akt; PUMA; apoptosis; colon cancer; p53