NQO1-induced activation of AMPK contributes to cancer cell death by oxygen-glucose deprivation.
NQO1-induced activation of AMPK contributes to cancer cell death by oxygen-glucose deprivation.
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DOI：
10.1038/srep07769
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发表时间：
2015-01-14
影响因子：
4.6
通讯作者：
Park HJ
中科院分区：
文献类型：
--
作者：
Lee H;Oh ET;Choi BH;Park MT;Lee JK;Lee JS;Park HJ
在实体瘤中，由于血液循环不足而导致的缺氧缺糖(OGD)会降低癌细胞的存活和增殖。OGD可增加细胞内[AMP]/[ATP]比值，从而激活AMPK。在这项研究中，我们研究了NQO1在OGD介导的AMPK激活和癌细胞死亡中的作用。我们发现OGD以NQO1依赖的方式激活AMPK，抑制控制细胞生存的mTOR/S6K/4E-BP1通路。因此，NQO1的缺失可以防止AMPK诱导的OGD癌细胞死亡。当我们阻断OGD诱导的Ca~(2+)/CaMKII信号通路时，NQO1诱导的AMPK激活被减弱。此外，当我们阻断RyR信号时，在OGD条件下，表达NQO1的细胞内钙离子的积累以及随后CaMKII/AMPK信号的激活都减少了。最后，siRNA介导的CD38下调可阻断OGD诱导的Ca~(2+)/CaMKII/AMPK信号的激活。综上所述，我们认为NQO1通过CD38/cADPR/RyR/Ca~(2+)/CaMKII信号通路在AMPK诱导的OGD癌细胞死亡中发挥关键作用。
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.
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影响因子：
6.2
作者：
Danilov, Camelia A.;Chandirasekaran, Krish;Racz, Jennifer;Soane, Lucian;Zielke, Carol;Fiskum, Gary
通讯作者：
Fiskum, Gary
影响因子：
4.8
作者：
Arsham, AM;Howell, JJ;Simon, MC
通讯作者：
Simon, MC
影响因子：
3.5
作者：
Davies, SP;Helps, NR;Hardie, DG
通讯作者：
Hardie, DG
影响因子：
4.8
作者：
Choi, Eun K.;Terai, Kaoru;Park, Heon Joo
通讯作者：
Park, Heon Joo
DOI：
10.1073/pnas.91.18.8413
发表时间：
1994-08-30
影响因子：
11.1
作者：
JOSEPH, P;JAISWAL, AK
通讯作者：
JAISWAL, AK