Inhibition of mTORC2 enhances UVB-induced apoptosis in keratinocytes through a mechanism dependent on the FOXO3a transcriptional target NOXA but independent of TRAIL.
Inhibition of mTORC2 enhances UVB-induced apoptosis in keratinocytes through a mechanism dependent on the FOXO3a transcriptional target NOXA but independent of TRAIL.
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DOI：
10.1016/j.cellsig.2018.08.018
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发表时间：
2018-12
影响因子：
4.8
通讯作者：
Shantz LM
中科院分区：
文献类型：
--
作者：
Feehan RP;Nelson AM;Shantz LM
非黑色素瘤皮肤癌（NMSC）的主要原因是紫外线B （UVB）辐射。我们之前已经证明，mTORC2抑制使角质形成细胞对由转录因子FOXO3a介导的uvb诱导的凋亡敏感。FOXO3a是几种癌症类型中细胞凋亡的关键调节因子和肿瘤抑制因子。FOXO3a的激活通过多种靶基因（包括TRAIL和NOXA）的协同表达促进细胞凋亡。我们假设在mTORC2抑制的情况下，uvb诱导的这些因子的表达会以foxo3a依赖的方式导致细胞凋亡。使用自发永生化的人角质形成细胞（HaCaT细胞），我们观察到暴露于UVB和TOR激酶抑制剂Torin-2的细胞中TRAIL和NOXA的表达均增加。与FOXO3a基因敲除类似，NOXA基因敲除逆转了mTORC2抑制对uvb诱导的细胞凋亡的致敏作用。相反，无论是敲低还是敲除，TRAIL的缺失实际上都增强了细胞核FOXO3a的表达，从而维持了细胞凋亡。这些令人惊讶的结果不是由于HaCaT细胞中错误的死亡受体信号，因为我们发现细胞在重组TRAIL处理后会发生外源性凋亡。更引人注目的是，与野生型HaCaT细胞相比，TRAIL敲除细胞对重组TRAIL诱导的凋亡更敏感，在mTORC2抑制的情况下增加最多。综上所述，这些研究提供了强有力的证据，mTORC2通过调节FOXO3a下游NOXA的表达来控制uvb诱导的细胞凋亡。此外，mTORC2抑制剂激活FOXO3a转录可能是预防或治疗NMSC的一个有价值的靶点，特别是在内源性TRAIL低的情况下。
The primary cause of non-melanoma skin cancer (NMSC) is ultraviolet B (UVB) radiation. We have shown previously that mTORC2 inhibition sensitizes keratinocytes to UVB-induced apoptosis mediated by the transcription factor FOXO3a. FOXO3a is a key regulator of apoptosis and a tumor suppressor in several cancer types. Activation of FOXO3a promotes apoptosis through the coordinated expression of a variety of target genes, including TRAIL and NOXA. We hypothesized that in the setting of mTORC2 inhibition, the UVB-induced expression of these factors would lead to apoptosis in a FOXO3a-dependent manner. Using spontaneously immortalized human keratinocytes (HaCaT cells), we observed that both TRAIL and NOXA expression increased in cells exposed to UVB and the TOR kinase inhibitor Torin-2. Similar to knockdown of FOXO3a, NOXA knockdown reversed the sensitization to UVB-induced apoptosis caused by mTORC2 inhibition. In contrast, loss of TRAIL by either knockdown or knockout actually enhanced expression of nuclear FOXO3a, which maintained apoptosis. These surprising results are not due to faulty death receptor signaling in HaCaT cells, as we found that the cells undergo extrinsic apoptosis in response to treatment with recombinant TRAIL. Even more striking, TRAIL knockout cells were sensitized to recombinant TRAIL-induced apoptosis compared to wild-type HaCaT cells, with the largest increase occurring in the presence of mTORC2 inhibition. Taken together, these studies provide strong evidence that mTORC2 controls UVB-induced apoptosis by regulating NOXA expression downstream of FOXO3a. Moreover, FOXO3a transcriptional activation by mTORC2 inhibitors may be a valuable target for prevention or therapy of NMSC, especially in cases with low endogenous TRAIL.
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DOI：
10.1158/1940-6207.capr-12-0272-t
发表时间：
2012-12
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Carr TD;DiGiovanni J;Lynch CJ;Shantz LM
通讯作者：
Shantz LM
影响因子：
4.7
作者：
Carr, Theresa D.;Feehan, Robert P.;Shantz, Lisa M.
通讯作者：
Shantz, Lisa M.
影响因子：
6.5
作者：
Bachmann, F;Buechner, SA;Erb, P
通讯作者：
Erb, P
影响因子：
5.6
作者：
Lee CH;Wu SB;Hong CH;Yu HS;Wei YH
通讯作者：
Wei YH
影响因子：
4.8
作者：
Feehan RP;Shantz LM
通讯作者：
Shantz LM