Protein kinase C as a tumor suppressor. (February 2018)

• Record Type: Journal Article
• Authors: Newton, Alexandra C.
• Is Part Of: Seminars in cancer biology. Volume 48(2018)
• Page Start: 18
• Page End: 26
• Publication Date: 2018-02
• Subjects: Aβ amyloid-β -- GOF gain-of-function -- JSLE juvenile systemic lupus erythematosus -- LOF loss-of-function -- mTORC mammalian target of rapamycin complex -- PB1 Phox and Bem1p -- PDBu phorbol 12, 13-dibutyrate -- PDK-1 phosphoinositide-dependent kinase-1 -- PIP2 phosphatidylinositol-4, 5-bisphosphate -- PKA protein kinase A -- PKB protein kinase B -- PKC protein kinase C -- PKN protein kinase N -- PMA phorbol 12-myristate 13-acetate; PKC -- Phorbol esters -- Tumor suppressor -- Diacylglycerol -- LOF; Cancer -- Periodicals; Neoplasms -- Periodicals; Review Literature; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.semcancer.2017.04.017
• Languages: English
• ISSNs: 1044-579X

Abstract

Abstract: Protein kinase C (PKC) has historically been considered an oncoprotein. This stems in large part from the discovery in the early 1980s that PKC is directly activated by tumor-promoting phorbol esters. Yet three decades of clinical trials using PKC inhibitors in cancer therapies not only failed, but in some cases worsened patient outcome. Why has targeting PKC in cancer eluded successful therapies? Recent studies looking at the disease for insight provide an explanation: cancer-associated mutations in PKC are generally loss-of-function (LOF), supporting an unexpected function as tumor suppressors. And, contrasting with LOF mutations in cancer, germline mutations that enhance the activity of some PKC isozymes are associated with degenerative diseases such as Alzheimer's disease. This review provides a background on the diverse mechanisms that ensure PKC is only active when, where, and for the appropriate duration needed and summarizes recent findings converging on a paradigm reversal: PKC family members generally function by suppressing, rather than promoting, survival signaling.