Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6418-23. doi: 10.1073/pnas.1221799110. Epub 2013 Apr 2.
Studies showing reduced PKCζ expression or enzymatic activity in different types of human cancers support the clinical relevance of PKCζ as a tumor suppressor. However, the in vivo role of PKCζ and its mechanisms of action in prostate cancer remain unclear. Here we demonstrate that the genetic inactivation of PKCζ in mice results in invasive prostate carcinoma in vivo in the context of phosphatase and tensin homolog deficiency. Bioinformatic analysis of human prostate cancer gene-expression sets revealed increased c-Myc transcriptional activity in PKCζ-inactive cells, which correlated with increased cell growth, invasion, and metastasis. Interestingly, PKCζ knockdown or the overexpression of a kinase-inactive mutant resulted in enhanced cell proliferation and invasion in vitro through increased c-Myc mRNA and protein levels and decreased Ser-373 phosphorylation of c-Myc. Analysis of prostate cancer samples demonstrated increased expression and decreased phosphorylation of c-Myc at Ser-373 in PKCζ knockout tumors. In vivo xenograft studies revealed that c-Myc phosphorylation by PKCζ is a critical event in the control of metastasis. Collectively, these results establish PKCζ as an important tumor suppressor and regulator of c-Myc function in prostate cancer.
研究表明，PKCζ 在不同类型的人类癌症中的表达或酶活性降低，支持 PKCζ 作为肿瘤抑制因子的临床相关性。然而，PKCζ 在前列腺癌中的体内作用及其作用机制仍不清楚。在这里，我们证明在磷酸酶和张力蛋白同源物缺陷的情况下，PKCζ 在小鼠中的基因失活导致体内侵袭性前列腺癌。对人类前列腺癌基因表达谱的生物信息学分析显示，在 PKCζ 失活的细胞中 c-Myc 转录活性增加，这与细胞生长、侵袭和转移增加相关。有趣的是，PKCζ 敲低或激酶失活突变体的过表达导致体外细胞增殖和侵袭增强，这是通过增加 c-Myc mRNA 和蛋白水平以及降低 c-Myc 的 Ser-373 磷酸化来实现的。对前列腺癌样本的分析表明，PKCζ 缺失肿瘤中 c-Myc 在 Ser-373 的表达增加和磷酸化减少。体内异种移植研究表明，PKCζ 对 c-Myc 的磷酸化是控制转移的一个关键事件。总之，这些结果确立了 PKCζ 作为前列腺癌中重要的肿瘤抑制因子和 c-Myc 功能的调节剂。
