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.
| Original language | English |
|---|---|
| Article number | 7769 |
| Journal | Scientific Reports |
| Volume | 5 |
| DOIs | |
| State | Published - 2015 |
| Externally published | Yes |
Bibliographical note
Funding Information:We gratefully thank Medical illustrator Ms. Seulki Jung (Department of Social Medicine, College of Medicine, Inha University, Republic of Korea) for making and providing illustration used on Figure 5J. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2014R1A5A2009392, NRF-2013M2A2A7043703 and 2012-M2B2B1-2012055637).
