TRAF6 regulates autophagy and apoptosis of melanoma cells through c-Jun/ATG16L2 signaling pathway.
TRAF6 regulates autophagy and apoptosis of melanoma cells through c-Jun/ATG16L2 signaling pathway.
复制标题
TRAF6通过c-Jun/ATG16L2信号通路调控黑色素瘤细胞的自噬和凋亡。
作者：
Guo, Yeye;Zhang, Xu;Li, Jie;Zhou, Zhe;Zhu, Susi;Liu, Waner;Su, Juan;Chen, Xiang;Peng, Cong
细胞自噬和细胞凋亡是参与细胞死亡和维持细胞稳态的重要过程。这些生物过程的失调会导致包括癌症在内的疾病的发展。因此，靶向细胞凋亡和自噬之间的相互作用为癌症治疗提供了一种潜在的策略。黑色素瘤是最致命的皮肤癌。我们之前发现肿瘤坏死因子受体相关因子6 （TRAF6）在黑色素瘤中过表达，有利于黑色素瘤细胞的恶性表型。此外，TRAF6促进黑色素瘤中癌症相关成纤维细胞的激活。然而，TRAF6在自噬和凋亡中的作用尚不清楚。在本研究中，我们发现TRAF6的下调可诱导黑色素瘤细胞凋亡和自噬。转录组学数据和实时PCR分析显示，在TRAF6缺失的黑色素瘤细胞中，自噬相关的16 like 2 （ATG16L2）的表达降低。ATG16L2敲低导致细胞自噬和凋亡增加。机制研究证实TRAF6通过c‐Jun调控ATG16L2的表达。重要的是，TRAF6抑制剂cinchonine靶向TRAF6，通过TRAF6/c‐Jun/ATG16L2信号通路诱导自噬和凋亡，有效抑制黑色素瘤细胞的生长。这些发现突出了TRAF6在调节黑色素瘤自噬和凋亡中的关键作用，强调了其作为黑色素瘤治疗新靶点的意义。TRAF6促进c - Jun的转录活性，导致ATG16L2的上调。该信号通路在黑色素瘤细胞凋亡和自噬的调控中起关键作用。cinchonine抑制TRAF6通过诱导细胞凋亡和自噬有效抑制黑色素瘤细胞生长。我们的研究结果强调了靶向TRAF6 - c - Jun/ATG16L2轴在黑色素瘤治疗中的治疗潜力。
Autophagy and apoptosis are essential processes that participate in cell death and maintain cellular homeostasis. Dysregulation of these biological processes results in the development of diseases, including cancers. Therefore, targeting the interaction between apoptosis and autophagy offers a potential strategy for cancer therapy. Melanoma is the most lethal skin cancer. We previously found that tumor necrosis factor receptor‐associated factor 6 (TRAF6) is overexpressed in melanoma and benefits the malignant phenotype of melanoma cells. Additionally, TRAF6 promotes the activation of cancer‐associated fibroblasts in melanoma. However, the role of TRAF6 in autophagy and apoptosis remains unclear. In this study, we found that knockdown of TRAF6 induced both apoptosis and autophagy in melanoma cells. Transcriptomic data and real‐time PCR analysis demonstrated reduced expression of autophagy related 16 like 2 (ATG16L2) in TRAF6‐deficient melanoma cells. ATG16L2 knockdown resulted in increased autophagy and apoptosis. Mechanism studies confirmed that TRAF6 regulated ATG16L2 expression through c‐Jun. Importantly, targeting TRAF6 with cinchonine, a TRAF6 inhibitor, effectively suppressed the growth of melanoma cells by inducing autophagy and apoptosis through the TRAF6/c‐Jun/ATG16L2 signaling pathway. These findings highlight the pivotal role of TRAF6 in regulating autophagy and apoptosis in melanoma, emphasizing its significance as a novel therapeutic target for melanoma treatment. TRAF6 promotes the transcriptional activity of c‐Jun, resulting in the upregulation of ATG16L2. This signaling pathway plays a pivotal role in the regulation of apoptosis and autophagy in melanoma cells. Inhibition of TRAF6 using cinchonine effectively suppresses melanoma cell growth by inducing apoptosis and autophagy. Our findings highlight the therapeutic potential of targeting the TRAF6‐c‐Jun/ATG16L2 axis in melanoma treatment.
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DOI：
10.1016/j.jid.2020.03.943
发表时间：
2021-01
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Jenkins RW;Fisher DE
通讯作者：
Fisher DE
影响因子：
--
作者：
Brentnall M;Rodriguez-Menocal L;De Guevara RL;Cepero E;Boise LH
通讯作者：
Boise LH
影响因子：
13.3
作者：
Akar, Ugur;Chaves-Reyez, Arturo;Ozpolat, Bulent
通讯作者：
Ozpolat, Bulent
影响因子：
6.5
作者：
Guo, Yeye;Zhang, Xu;Peng, Cong
通讯作者：
Peng, Cong
影响因子：
5.2
作者：
Busch J;Moreno R;de la Vega L;Saul VV;Bacher S;von Zweydorf F;Ueffing M;Weber A;Gloeckner CJ;Linne U;Kracht M;Schmitz ML
通讯作者：
Schmitz ML