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Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression
1The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences and the Cancer Research Center, Ben Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel.
Abstract:
The AGC family of serine/threonine kinases (PKA, PKG, PKC) includes more than 60 members that are critical regulators of numerous cellular functions, including cell cycle and differentiation, morphogenesis, and cell survival and death. Mutation and/or dysregulation of AGC kinases can lead to malignant cell transformation and contribute to the pathogenesis of many human diseases. Members of one subgroup of AGC kinases, the protein kinase C (PKC), have been singled out as critical players in carcinogenesis, following their identification as the intracellular receptors of phorbol esters, which exhibit tumor-promoting activities. This observation attracted the attention of researchers worldwide and led to intense investigations on the role of PKC in cell transformation and the potential use of PKC as therapeutic drug targets in cancer diseases. Studies demonstrated that many cancers had altered expression and/or mutation of specific PKC genes. However, the causal relationships between the changes in PKC gene expression and/or mutation and the direct cause of cancer remain elusive. Independent studies in normal cells demonstrated that activation of PKC is essential for the induction of cell activation and proliferation, differentiation, motility, and survival. Based on these observations and the general assumption that PKC isoforms play a positive role in cell transformation and/or cancer progression, many PKC inhibitors have entered clinical trials but the numerous attempts to target PKC in cancer has so far yielded only very limited success. More recent studies demonstrated that PKC function as tumor suppressors, and suggested that future clinical efforts should focus on restoring, rather than inhibiting, PKC activity. The present manuscript provides some historical perspectives on the tumor promoting function of PKC, reviewing some of the observations linking PKC to cancer progression, and discusses the role of PKC in the pathogenesis of cancer diseases and its potential usage as a therapeutic target.
Insights
Protein kinase C (PKC) has a complex role in cancer, initially viewed as a tumor promoter but now recognized for potential tumor-suppressing functions. Future cancer therapies may involve restoring PKC activity, not inhibiting it.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The AGC kinase family, including protein kinase C (PKC), regulates vital cellular processes.
- PKC was initially implicated in cancer due to its role in cell transformation and response to tumor promoters.
- Altered PKC expression is observed in many cancers, but its direct causal role remains unclear.
Purpose of the Study:
- To review the historical perspective of PKC's dual role in cancer.
- To discuss the link between PKC and cancer progression.
- To explore PKC as a potential therapeutic target in oncology.
Main Methods:
- Literature review of historical and recent studies on PKC in cancer.
- Analysis of research linking PKC gene expression/mutation to cancer pathogenesis.
- Discussion of clinical trial outcomes for PKC inhibitors.
Main Results:
- PKC was historically considered a tumor promoter, driving cell proliferation and survival.
- Many attempts to inhibit PKC in cancer have shown limited success.
- Emerging evidence suggests PKC may act as a tumor suppressor in certain contexts.
Conclusions:
- PKC's role in cancer is complex and context-dependent, shifting from promoter to potential suppressor.
- Targeting PKC in cancer requires a nuanced approach, possibly focusing on restoring function.
- Further research is needed to elucidate the precise mechanisms and therapeutic potential of PKC in cancer treatment.
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