title: DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells.
abstract: Pancreatic cancer is one of the most aggressive human malignancies with extremely poor prognosis. The moderate activity of the current standard gemcitabine and gemcitabine-based regimens was due to pre-existing or acquired chemo-resistance of pancreatic cancer cells. In this study, we explored the potential role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in gemcitabine resistance, and studied the underlying mechanisms. We found that NU-7026 and NU-7441, two DNA-PKcs inhibitors, enhanced gemcitabine-induced cytotoxicity and apoptosis in PANC-1 pancreatic cancer cells. Meanwhile, PANC-1 cells with siRNA-knockdown of DNA-PKcs were more sensitive to gemcitabine than control PANC-1 cells. Through the co-immunoprecipitation (Co-IP) assay, we found that DNA-PKcs formed a complex with SIN1, the latter is an indispensable component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). DNA-PKcs-SIN1 complexation was required for Akt activation in PANC-1 cells, while inhibition of this complex by siRNA knockdown of DNA-PKcs/SIN1, or by DNA-PKcs inhibitors, prevented Akt phosphorylation in PANC-1 cells. Further, SIN1 siRNA-knockdown also facilitated gemcitabine-induced apoptosis in PANC-1 cells. Finally, DNA-PKcs and p-Akt expression was significantly higher in human pancreatic cancer tissues than surrounding normal tissues. Together, these results show that DNA-PKcs is important for Akt activation and gemcitabine resistance in PANC-1 pancreatic cancer cells.
authors.affiliation: The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province 214000, China. Electronic address: haoge123478@163.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province 214000, China.
authors.forename: Yuanlong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province 214000, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qian
authors.affiliation: The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province 214000, China.
authors.forename: Benshun
authors.initials: B
authors.lastname: Hu
authors.affiliation: The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province 214000, China.
authors.forename: Congyuan
authors.initials: C
authors.lastname: Zhu
authors.affiliation: The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province 214000, China.
authors.forename: Gaohe
authors.initials: G
authors.lastname: Wang
authors.affiliation: The Hepatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province 214000, China. Electronic address: jianpingwuxi1974@126.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D051747:DNA-Activated Protein Kinase; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine
keywords: Akt and chemo-resistance; DNA-PKcs; Gemcitabine; Pancreatic cancer