Tumor-specific p73 up-regulation mediates p63 dependence in squamous cell carcinoma
Tumor-specific p73 up-regulation mediates p63 dependence in squamous cell carcinoma
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DOI：
10.1158/0008-5472.can-06-1619
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Ellisen, Leif W.
中科院分区：
文献类型：
--
作者：
DeYoung, Maurice Phillip;Johannessen, Cory M.;Ellisen, Leif W.
P63对于正常的上皮发育是必不可少的，并且在绝大多数鳞状细胞癌(SCC)中过表达。最近的研究表明，ANp63eL对于SCC细胞的生存是必不可少的，这增加了p63通路可能是这些肿瘤有吸引力的治疗靶点的可能性。然而，目前尚不清楚是否存在抑制肿瘤细胞和正常上皮中p63的治疗窗口。在这里，我们证明了SCC细胞唯一地依赖Delta Np63α生存，不同于正常的p63表达的上皮细胞，这种依赖是通过肿瘤特异性上调相关蛋白p73来介导的。在正常的原代人角质形成细胞中，我们发现通过RNA干扰(RNAi)抑制内源性p63诱导p21(CIP1)表达，抑制细胞周期进展，最终促进细胞衰老。相反，抑制鳞状细胞癌细胞中的p63可诱导促凋亡的bcl2家族成员，并迅速触发细胞凋亡。P73在未培养的基底层角质形成细胞中低表达，但在体内SCC细胞系和原发肿瘤中明显上调。在正常细胞中，p63缺失后p21(CIP1)的诱导不依赖于p53和p73，而在肿瘤细胞中，p63 RNAi诱导的促凋亡基因和细胞死亡都依赖于p73。最后，p73在原代角质形成细胞中的异位表达不会影响基线细胞的增殖，但足以在p63丢失后引发细胞死亡。综上所述，这些发现明确了p63依赖通过p73上调的特定分子机制，并为将p63通路作为SCC治疗策略提供了理论基础。
p63 is essential for normal epithelial development and is overexpressed in the vast majority of squamous cell carcinomas (SCC). Recent work had shown that ANp63eL is essential for survival of SCC cells, raising the possibility that the p63 pathway may be an attractive therapeutic target in these tumors. Nevertheless, it is unknown whether a therapeutic window exists for inhibiting p63 in tumor cells versus normal epithelia. Here, we show that SCC cells are uniquely dependent on Delta Np63 alpha for survival, unlike normal p63-expressing epithelial cells, and that dependence is mediated through tumor-specific up-regulation of the related protein p73. In normal primary human keratinocytes, we find that inhibition of endogenous p63 by RNA interference (RNAi) induces p21(CIP1) expression, inhibits cell cycle progression, and ultimately promotes cellular senescence. In contrast, p63 inhibition in SCC cells induces proapoptotic bcl-2 family members and rapidly triggers apoptosis. Expression of p73 is low in uncultured basal keratinocytes but is markedly up-regulated in both SCC cell lines and primary tumors in vivo. Whereas p21(CIP1) induction following loss of p63 in normal cells is independent of p53 and p73, both proapoptotic gene induction and cell death following p63 RNAi in tumor cells are p73 dependent. Finally, ectopic p73 expression in primary keratinocytes does not affect baseline cell proliferation but is sufficient to trigger cell death following loss of p63. Together, these findings define a specific molecular mechanism of p63 dependence through p73 up-regulation, and they provide a rationale for targeting the p63 pathway as a therapeutic strategy in SCCs.