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.

Keywords: cancer therapy; oncogene; phorbol esters; protein kinase C; tumor promoter; tumor suppressor.

Figure 1. Protein families with phorbol ester/DAG responsive C1 domains

Diagram of protein families with C1 domains that bind phorbol esters and diacylglycerol (DAG). DAG is generated upon stimulation of membrane receptors such as tyrosine-kinase and G-protein-coupled receptors. C1, C1 domain; C2, C2 domain; PS, pseudosubstrate domain; PH, pleckstrin homology domain; EF, EF hands; SH2, Src-homology 2 domain; Rac-GAP, Rac GTPase Activating Protein domain; REM, Ras Exchanger Motif; RasGEF, Ras Guanine nucleotide Exchange Factor domain. Note that the figure depicts representative structures for each class, but certain members lack some of these domains or may contain additional domains not depicted here.

Figure 2. PKC isozymes as regulators of cellular function and cancer progression

PKCs control multiple functions associated with cancer progression, in many cases in opposite manners. Depending on the context, PKCs can act either as promoters or suppressors of the cancer phenotype.