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首页> 外文期刊>Cellular Signalling >Inhibition of mTORC2 enhances UVB-induced apoptosis in keratinocytes heck fo through a mechanism dependent on the FOXO3a transcriptional target NOXA but independent of TRAIL
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Inhibition of mTORC2 enhances UVB-induced apoptosis in keratinocytes heck fo through a mechanism dependent on the FOXO3a transcriptional target NOXA but independent of TRAIL

机译：通过依赖于Foxo3A转录靶NOXA的机制，抑制MTORC2在角蛋白细胞Heck FO中增强了UVB诱导的凋亡凋亡，但独立于TRAIL

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摘要

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.
机译：非黑色素瘤皮肤癌（NMSC）的主要原因是紫外线B（UVB）辐射。我们以前表明，MTORC2抑制剂使角质形成细胞敏感到由转录因子FoxO3A介导的UVB诱导的细胞凋亡。 FOXO3A是几种癌症类型细胞凋亡和肿瘤抑制剂的关键调节因子。通过各种靶基因的协调表达，促进FOXO3A的激活促进细胞凋亡，包括痕迹和NOXA。我们假设在MTORC2抑制的设置中，UVB诱导的这些因子的表达将导致依赖于FoxO3A依赖性的凋亡。使用自发的永生化的人角蛋白细胞（HACAT细胞），观察到，在暴露于UVB的细胞和TOR激酶抑制剂TORIN 2中的痕迹和NOXA表达增加2.类似于FOXO3A的敲低，NOXA敲低逆转了对UVB诱导的细胞凋亡的敏化mtorc2抑制。相比之下，通过敲低或敲除陷入困境的损失实际上增强了核Foxo3a的表达，这维持了凋亡。这些令人惊讶的结果不是由于HaCAT细胞中的死亡受体信号传导错误，因为我们发现细胞经历外在凋亡，以应对重组痕迹的治疗。与野生型HACAT细胞相比，甚至更醒目的径敲除细胞被敏感到重组尾部诱导的细胞凋亡，在MTORC2抑制存在下发生的最大增加。这些研究总结在一起，提供了强有力的证据，即MTORC2通过调节FOXO3A下游的NOXA表达来控制UVB诱导的细胞凋亡。此外，MTORC2抑制剂的FOXO3A转录激活可以是用于预防或治疗NMSC的有价值的靶标，特别是在具有低内源性痕迹的情况下。

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