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The PKC universe keeps expanding: From cancer initiation to metastasis
Nilufar Rahimova1, Mariana Cooke2, Suli Zhang1
1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Abstract:
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.
Insights
Classical and novel protein kinase C (PKC) isozymes are involved in cancer initiation and metastasis. These PKC isozymes regulate cell motility, invasion, and potentially immune evasion, offering new therapeutic targets.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Classical and novel protein kinase C (PKC) isozymes (c/nPKCs) are activated by diacylglycerol (DAG) and phorbol esters.
- While traditionally linked to tumor promotion, c/nPKCs also exhibit tumor-suppressing roles and participate in various carcinogenesis stages.
- Their functions extend beyond promotion, influencing cellular proliferation and motility.
Purpose of the Study:
- To review the complex roles of c/nPKCs in cancer initiation and the metastatic cascade.
- To emphasize c/nPKC involvement in cancer cell motility through regulation of Rho GTPases, ECM-degrading proteases, and epithelial-to-mesenchymal transition (EMT).
- To explore the potential role of c/nPKCs in anticancer drug resistance and immune evasion via immune checkpoint protein expression.
Main Methods:
- Literature review and synthesis of existing research on c/nPKC functions in cancer.
- Analysis of signaling pathways regulated by c/nPKCs, including Rho GTPases and EMT.
- Examination of evidence linking c/nPKCs to drug resistance and immune evasion.
Main Results:
- c/nPKCs play multifaceted roles in cancer, including initiation, promotion, and suppression.
- PKCα and PKCε are highlighted for their interplay with mesenchymal features, contributing to invasion and potential drug resistance.
- c/nPKCs may regulate immune checkpoint proteins, suggesting a role in immune evasion.
Conclusions:
- Dissecting c/nPKC signaling complexity is crucial for understanding cancer progression.
- c/nPKCs offer potential targets for developing novel cancer prognosis and therapeutic strategies.
- Further research into c/nPKC roles in drug resistance and immune evasion is warranted.
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