The PKC Universe Keeps Expanding: From Cancer Initiation to Metastasis

Classical and novel protein kinase C (PKC) isozymes (c/nPKCs), members of the PKC family that become activated by the lipid second messenger diacylglycerol (DAG) and phorbol esters, exert a myriad of cellular effects that impact proliferative and motile cellular responses. While c/nPKCs have been indisputably associated with tumor promotion, their roles exceed by far their sole involvement as promoter kinases. Indeed, this original dogma has been subsequently redefined by the introduction of several new concepts: the identification of tumor suppressing roles for c/nPKCs, and their participation in early and late stages of carcinogenesis. This review dives deep into the intricate roles of c/nPKCs in cancer initiation as well as in the different stages of the metastatic cascade, with great emphasis in their involvement in cancer cell motility via regulation of small Rho GTPases, the production of extracellular matrix (ECM)-degrading proteases, and the epithelial-to-mesenchymal transition (EMT) program required for the acquisition of highly invasive traits. Here, we highlight functional interplays between either PKCα or PKCε and mesenchymal features that may ultimately contribute to anticancer drug resistance in cellular and animal models. We also introduce the novel hypothesis that c/nPKCs may be implicated in the control of immune evasion through the regulation of immune checkpoint protein expression. In summary, dissecting the colossal complexity of c/nPKC signaling in the wide spectrum of cancer progression may bring new opportunities for the development of meaningful tools aiding for cancer prognosis and therapy.