Ku70 inhibits gemcitabine-induced DNA damage and pancreatic cancer cell apoptosis.
The current study focused on the role of Ku70, a DNA-dependent protein kinase (DNA-PK) complex protein, in pancreatic cancer cell resistance to gemcitabine. In both established cell lines (Mia-PaCa-2 and PANC-1) and primary human pancreatic cancer cells, shRNA/siRNA-mediated knockdown of Ku70 significantly sensitized gemcitabine-induced cell death and proliferation inhibition. Meanwhile, gemcitabine-induced DNA damage and subsequent pancreatic cancer cell apoptosis were also potentiated with Ku70 knockdown. On the other hand, exogenous overexpression of Ku70 in Mia-PaCa-2 cells suppressed gemcitabine-induced DNA damage and subsequent cell apoptosis. In a severe combined immune deficient (SCID) mice Mia-PaCa-2 xenograft model, gemcitabine-induced anti-tumor activity was remarkably pontificated when combined with Ku70 shRNA knockdown in the xenografts. The results of this preclinical study imply that Ku70 might be a primary resistance factor of gemcitabine, and Ku70 silence could significantly chemo-sensitize gemcitabine in pancreatic cancer cells.
Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
Jiali
J
Ma
Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
Pingping
P
Hui
Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
Wenying
W
Meng
Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
Na
N
Wang
Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China. Electronic address: shihaoxiangtrsh@yeah.net.
Shihao
S
Xiang
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000072200:Ku Autoantigen; D000093542:Gemcitabine
Chemo-sensitization; DNA damage; Gemcitabine; Ku70; Pancreatic cancer