Garg Rachana, Blando Jorge M, Perez Carlos J, Abba Martin C, Benavides Fernando, Kazanietz Marcelo G
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Immunopathology Laboratory, Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Rep. 2017 Apr 11;19(2):375-388. doi: 10.1016/j.celrep.2017.03.042.
PKCε, an oncogenic member of the PKC family, is aberrantly overexpressed in epithelial cancers. To date, little is known about functional interactions of PKCε with other genetic alterations, as well as the effectors contributing to its tumorigenic and metastatic phenotype. Here, we demonstrate that PKCε cooperates with the loss of the tumor suppressor Pten for the development of prostate cancer in a mouse model. Mechanistic analysis revealed that PKCε overexpression and Pten loss individually and synergistically upregulate the production of the chemokine CXCL13, which involves the transcriptional activation of the CXCL13 gene via the non-canonical nuclear factor κB (NF-κB) pathway. Notably, targeted disruption of CXCL13 or its receptor, CXCR5, in prostate cancer cells impaired their migratory and tumorigenic properties. In addition to providing evidence for an autonomous vicious cycle driven by PKCε, our studies identified a compelling rationale for targeting the CXCL13-CXCR5 axis for prostate cancer treatment.
蛋白激酶Cε（PKCε）是PKC家族的一个致癌成员，在上皮癌中异常过度表达。迄今为止，关于PKCε与其他基因改变的功能相互作用，以及导致其致瘤和转移表型的效应分子，我们知之甚少。在此，我们证明在小鼠模型中，PKCε与肿瘤抑制因子Pten的缺失协同作用促进前列腺癌的发生。机制分析表明，PKCε的过表达和Pten的缺失分别及协同上调趋化因子CXCL13的产生，这涉及通过非经典核因子κB（NF-κB）途径对CXCL13基因的转录激活。值得注意的是，在前列腺癌细胞中靶向破坏CXCL13或其受体CXCR5会损害它们的迁移和致瘤特性。除了为PKCε驱动的自主恶性循环提供证据外，我们的研究还为靶向CXCL13-CXCR5轴进行前列腺癌治疗提供了令人信服的理论依据。
