Identification of NME5 as a contributor to innate resistance to gemcitabine in pancreatic cancer cells.
The limited therapeutic effect of gemcitabine on pancreatic cancer is largely attributed to pre-existing or acquired resistance of the tumor cells. This study was aimed at screening for candidate resistance-related gene(s) and elucidating the underlying mechanisms. NME5 was found to be highly expressed in an innate gemcitabine-resistant human pancreatic cancer sample and the cell line PAXC002 derived from the sample. Downregulation of NME5 significantly reversed gemcitabine resistance in PAXC002 cells, whereas NME5 overexpression induced gemcitabine resistance in the pancreatic cancer cell line BxPC-3. NME5 attenuated the induction of apoptosis and cell cycle arrest induced by gemcitabine, probably accounting for the blunted sensitivity to gemcitabine. Furthermore, NME5 was demonstrated to play its role in a nuclear factor kappaB (NF-κB)-dependent manner. NME5 was capable of directly binding NF-κB, and possibly regulated its expression level in PAXC002 cells. Our results also suggest that NF-κB is a key executor of NME5 in regulating apoptosis and cell cycle. All of these data suggest that NME5 is a promising target for relieving innate gemcitabine resistance in pancreatic cancer cells.
Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
Fu
F
Li
Gang
G
Hu
Zhenzhou
Z
Jiang
Jingjing
J
Guo
Ke
K
Wang
Kedong
K
Ouyang
Danyi
D
Wen
Minghua
M
Zhu
Jiaxin
J
Liang
Xiaoran
X
Qin
Luyong
L
Zhang
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D016328:NF-kappa B; D054778:NM23 Nucleoside Diphosphate Kinases; C517948:NME5 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine