Cooperativity between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer
Posted December 8, 2017
Marcelo G. Kazanietz, Ph.D., University of Pennsylvania
Rachana Garg, Ph.D., University of Pennsylvania
Protein kinase C epsilon (PKCε), an oncogenic member of the protein kinase gene family, has been shown to be involved in the tumorigenesis of many cancer types, including prostate cancer (PCa). In PCa cells, PKCε is expressed at much higher levels than in normal prostate cells and helps the cancer cells to survive and proliferate. Previous findings by Dr. Marcelo Kazanietz and his laboratory at the University of Pennsylvania showed that when PKCε is expressed in normal prostate cells, it is sufficient to promote cell growth and increase known pro-survival genes. However, much is still unknown about how PKCε influences the action of other oncogenic and tumor suppressive alterations that commonly occur in PCa. Further elucidation on the mechanism of PCKε and its interaction with other genes may ultimately lead to novel drug targets to treat PCa patients.
With funding from a FY13 Idea Development Award and a FY11 Postdoctoral Training Award to Dr. Rachana Garg, the Kazanietz laboratory utilized a battery of cellular, biochemical, and molecular profiling approaches and found that PKCε cooperates with the loss of a tumor suppressor gene, Pten, to confer an enhanced proliferative, metastatic and invasive phenotype of PCa. This is highly relevant because loss of Pten is a common event in PCa patients, particularly those with advanced disease. They found that Pten-deficient prostate cell lines engineered to overexpress PKCε become highly invasive and tumorigenic, an indication that both alterations commonly observed in prostate tumors work together to promote the progression of PCa. Additionally, they identified genes that change their expression as a consequence of PKCε overexpression and/or Pten loss. In particularly, they found that chemokine CXCL13 was often unregulated.
Identification of the chemokine CXCL13 as an effector of PKCε overexpression and Pten loss has potential significant therapeutic implications. The novel molecular insights that the Kazanietz laboratory identified may be important in designing new classes of drugs that could potentially block the CXCL13 pathway and act as effective anti-PCa agents. This research team is currently working towards this goal of ultimately helping to treat patients with PCa.
PKCε overexpression with Pten loss leads to CXCL13 upregulation via NF-kB
Gutierrez-Uzquiza A, Lopez-Haber C, Jernigan DL, et al. 2015. PKC is an essential mediator of prostate cancer bone metastasis. Mol Cancer Res 13:1336-1346.
Garg R, Blando J, Perez C et al. 2017. Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13- CXCR5 Pathway. Cell Reports 19, 375–388
Last updated Friday, December 8, 2017