title: NQO1-induced activation of AMPK contributes to cancer cell death by oxygen-glucose deprivation.
abstract: Oxygen and glucose deprivation (OGD) due to insufficient blood circulation can decrease cancer cell survival and proliferation in solid tumors. OGD increases the intracellular [AMP]/[ATP] ratio, thereby activating the AMPK. In this study, we have investigated the involvement of NQO1 in OGD-mediated AMPK activation and cancer cell death. We found that OGD activates AMPK in an NQO1-dependent manner, suppressing the mTOR/S6K/4E-BP1 pathway, which is known to control cell survival. Thus, the depletion of NQO1 prevents AMPK-induced cancer cell death in OGD. When we blocked OGD-induced Ca(2+)/CaMKII signaling, the NQO1-induced activation of AMPK was attenuated. In addition, when we blocked the RyR signaling, the accumulation of intracellular Ca(2+) and subsequent activation of CaMKII/AMPK signaling was decreased in NQO1-expressing cells under OGD. Finally, siRNA-mediated knockdown of CD38 abrogated the OGD-induced activation of Ca(2+)/CaMKII/AMPK signaling. Taken together, we conclude that NQO1 plays a key role in the AMPK-induced cancer cell death in OGD through the CD38/cADPR/RyR/Ca(2+)/CaMKII signaling pathway.
authors.affiliation: Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea.
authors.forename: Hyemi
authors.initials: H
authors.lastname: Lee
authors.affiliation: 1] Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea [2] Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, Korea.
authors.forename: Eun-Taex
authors.initials: ET
authors.lastname: Oh
authors.affiliation: 1] Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea [2] Pohang Center for Evaluation of Biomaterials, Pohang Technopark, Pohang, Gyeongbuk, Korea.
authors.forename: Bo-Hwa
authors.initials: BH
authors.lastname: Choi
authors.affiliation: 1] Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea [2] Research Center, Dongnam Institute of Radiological &Medical Sciences (DIRAMS), Busan, Korea.
authors.forename: Moon-Taek
authors.initials: MT
authors.lastname: Park
authors.affiliation: 1] Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, Korea [2] Department of Anatomy, College of Medicine, Inha University, Incheon, Korea.
authors.forename: Ja-Kyeong
authors.initials: JK
authors.lastname: Lee
authors.affiliation: 1] Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, Korea [2] Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea.
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: 1] Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea [2] Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, Korea.
authors.forename: Heon Joo
authors.initials: HJ
authors.lastname: Park
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D034741:RNA, Small Interfering; D009243:NAD; D036563:Cyclic ADP-Ribose; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D055372:AMP-Activated Protein Kinases; D051997:ADP-ribosyl Cyclase 1; D005947:Glucose; D010100:Oxygen; D002118:Calcium