Restored expression of the atypical heat shock protein H11/HspB8 inhibits the growth of genetically diverse melanoma tumors through activation of novel TAK1-dependent death pathways.
Restored expression of the atypical heat shock protein H11/HspB8 inhibits the growth of genetically diverse melanoma tumors through activation of novel TAK1-dependent death pathways.
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DOI：
10.1038/cddis.2012.108
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发表时间：
2012-08-16
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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黑色素瘤是一种侵袭性和耐药的癌症，需要改进治疗策略。恢复转录沉默基因的表达是一种潜在的方法，但它受到黑色素瘤肿瘤遗传多样性的限制。非典型热休克蛋白H11/HspB8具有激酶活性，并通过异常DNA甲基化在黑色素瘤中沉默。我们报道，它的恢复表达诱导了遗传多样性黑色素瘤系的死亡，并通过激活新的tak1依赖性死亡途径抑制肿瘤生长。这些包括(i) caspase-1通过上调含有CARD的凋亡相关斑点样蛋白（ASC）而独立于炎性体的激活，（ii）通过哺乳动物雷帕霉素靶蛋白（mTOR）在S2481位点的磷酸化而上调Beclin-1，以及（iii）由caspase-1介导的Beclin-1切割引起的细胞凋亡。这些数据扩展了目前对细胞死亡相关功能的理解，强调了H11/HspB8的强大治疗前景，并确定TAK1是黑色素瘤的潜在干预靶点。
Melanoma is an aggressive and drug-resistant cancer in need of improved therapeutic strategies. Restored expression of transcriptionally silenced genes is a potential approach, but it is limited by the genetic diversity of the melanoma tumors. The atypical heat shock protein H11/HspB8 has kinase activity and is silenced in melanoma through aberrant DNA methylation. We report that its restored expression induces the death of genetically diverse melanoma lines and inhibits tumor growth through the activation of novel TAK1-dependent death pathways. These include (i) caspase-1 activation independent of the inflammasome through upregulation of apoptosis-associated speck-like protein containing a CARD (ASC), (ii) Beclin-1 upregulation through phosphorylation of mammalian target of rapamycin (mTOR) at S2481 and (iii) apoptosis caused by caspase-1-mediated Beclin-1 cleavage. These data extend current understanding of cell death-associated functions, underscore the strong therapeutic promise of H11/HspB8 and identify TAK1 as a potential intervention target in melanoma.
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影响因子：
2.2
作者：
Panka DJ;Sullivan RJ;Mier JW
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