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 Ca2+/CaMKII signaling, the NQO1-induced activation of AMPK was attenuated. In addition, when we blocked the RyR signaling, the accumulation of intracellular Ca2+ 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 Ca2+/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/Ca2+/CaMKII signaling pathway.
Highlights
Oxygen and glucose deprivation (OGD) due to insufficient blood circulation can decrease cancer cell survival and proliferation in solid tumors
Consistent with a previous study showing that NAD(P)H:quinone oxidoreductase 1 (NQO1) activity is increased by OGD26, we found that NQO1 activity significantly increased after exposure of cells to OGD for 1 h, gradually declined thereafter among cells still under OGD (Figure 1C)
Since inhibition of mTOR through activation of the AMPK-TSC2 pathway has been shown to suppress the initiation of mRNA translation and ribosome biogenesis[31,32], we investigated the effect of NQO1 on the activation of mTOR under OGD
Summary
Oxygen and glucose deprivation (OGD) due to insufficient blood circulation can decrease cancer cell survival and proliferation in solid tumors. We conclude that NQO1 plays a key role in the AMPK-induced cancer cell death in OGD through the CD38/cADPR/RyR/Ca21/CaMKII signaling pathway. Oxygen and glucose deprivation (OGD) causes metabolic stresses that interfere with ATP, increasing the [AMP]/[ATP] ratio and activating AMP-activated protein kinase (AMPK)[2]. Diverse target proteins of AMPK have recently been reported to be involved in regulating cancer cell death or survival. AMPK has been shown to inhibit the proliferation and survival of cancer cells by suppressing mTOR (mammalian target of rapamycin) and its downstream regulators, S6K (ribosomal protein S6 kinase) and 4E-BP1 (eukaryotic initiation factor 4E binding protein 1)[12,13]. We report for the first time that OGD activates AMPK through the CD38/cADPR/RyR/Ca21/CaMKII signaling pathway, leading to the NQO1-dependent inactivation of mTOR. Our results clearly demonstrate that NQO1 plays a key role in OGD-induced cell death, and that this occurs via the activation of AMPK
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