Protein kinase C in cancer: The top five unanswered questions

Abstract

Few kinases have been studied as extensively as protein kinase C (PKC), particularly in the context of cancer. As major cellular targets for the phorbol ester tumor promoters and diacylglycerol (DAG), a second messenger generated by stimulation of membrane receptors, PKC isozymes play major roles in the control of signaling pathways associated with proliferation, migration, invasion, tumorigenesis, and metastasis. However, despite decades of research, fundamental questions remain to be answered or are the subject of intense controversy. Primary among these unresolved issues are the role of PKC isozymes as either tumor promoter or tumor suppressor kinases and the incomplete understanding on isozyme-specific substrates and effectors. The involvement of PKC isozymes in cancer progression needs to be reassessed in the context of specific oncogenic and tumor suppressing alterations. In addition, there are still major hurdles in addressing isozyme-specific function due to the limited specificity of most pharmacological PKC modulators and the lack of validated predictive biomarkers for response, which impacts the translation of these agents to the clinic. In this review we focus on key controversial issues and upcoming challenges, with the expectation that understanding the intricacies of PKC function will help fulfill the yet unsuccessful promise of targeting PKCs for cancer therapeutics.

Characterization of AJH-836, a diacylglycerol-lactone with selectivity for novel PKC isozymes

“…Thus, individual PKC isoforms have been shown to confer distinctive patterns of cellular responses, and the differences between isoforms may be dramatic. Depending on cellular context, PKC␣, PKC␦, and PKC⑀, the most commonly expressed PKCs, can trigger mitogenic/tumor-promoting or conversely antimitogenic/ tumor suppressor responses (3,12,13). A prediction is that ligands binding to typical C1 domains with differential selectivity could therefore induce distinct patterns of biological response.…”

“…A daunting challenge in the development of inhibitors for kinases has proven to be the large size of the kinome and the high homology in the ATP-binding site in the kinase domain (12,18). Although the high structural similarities among the binding clefts of C1 domains might a priori suggest similar problems, several factors provide encouragement.…”

“…Although the high structural similarities among the binding clefts of C1 domains might a priori suggest similar problems, several factors provide encouragement. Most importantly, natural products such as prostratin, bryostatin 1, and ingenol 3-angelate have unambiguously proven that C1-targeted ligands can achieve differential biological outcomes (12)(13)(14)(15)(16)(17)(18). Deeper consideration of the mechanism provides a rationale.…”

“…Second, it is appreciated that different ligands can cause different depths of insertion, changing these interactions. Furthermore, there is considerable diversity between cellular membranes or between microdomains within the membrane, changing the lipid environment with which the interactions will take place (5,12,19,20).…”

Cytosolic Ca2+modulates Golgi structure through PKC-mediated GRASP55 phosphorylation

“…Knockdown of atypical PKCs (aPKCs) using siRNA causes a reduction in peripheral ERGIC-53 clusters without affecting the Golgi morphology (32). In addition, increased PKC activity has been implicated in cancer (33,34), but the mechanism by which PKC may contribute to invasion, inflammation, tumorigenesis, and metastasis is not fully understood (35).…”