TUMOUR REVIEW
Exploitation of protein kinase C: A useful target for cancer therapy

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Summary

Protein kinase C is a family of serine/threonine kinases. The PKC family is made up of at least 12 isozymes, which have a role in cell proliferation, differentiation, angiogenesis, and apoptosis. Activation of PKC isozyme is dependent on tyrosine-kinase receptors and G-protein-coupled receptors. PKC isozymes regulate multiple signaling pathways including PI3-K/Akt, MAPK, and GSK-3β. PKC isozymes have variable roles in tumor biology which in part depend on the cell type and intracellular localization. PKC isozymes are commonly dysregulated in the cancer of the prostate, breast, colon, pancreatic, liver, and kidney. Currently, several classes of PKC inhibitors are being evaluated in clinical trials and several challenges in targeting PKC isozymes have been recently identified. In conclusion, PKC remains a promising target for cancer prevention and therapy.

Introduction

In the early 1980s, protein kinase C (PKC) was identified as the signaling pathway involved in the carcinogenic effects of phorbol esters.1, 2 The identification of the link between PKC and cancer, lead several researchers to focus on understanding the role of this signaling pathway. It is now well established that the PKC is a family of at least 12 serine threonine kinases.3 PKC isozymes have a central role in cellular signaling transduction involved in cell proliferation, differentiation, apoptosis and angiogenesis.4 Dysregulation of PKC activity and expression has been reported in several malignancies. Consequently, PKC has become a therapeutic target for the treatment of cancer.

Different strategies have been devised in the drug development of PKC inhibitors and these include small molecule kinase inhibitors, biologic modulators of PKC, and anti-sense oligonucleotides. These classes of agents differ in their spectrum of inhibition of PKC isozymes with anti-sense oligonucleotides being very specific biological agents but least specific. Several PKC inhibitors have been evaluated in clinical trials in different cancer types. The overwhelming results of these trials have been disappointing. The challenges in targeting PKC signaling pathway in clinical trials include the complexity and tissue specific role of PKC isozymes, limited in vivo information on the role of PKC, and lack of useful biomarkers of activity of PKC inhibitors. Despite these challenges facing researchers, PKC remains an important signaling pathway for the understanding of the biology of cancer and for future drug development.

Section snippets

PKC Isozymes and its downstream signaling

PKC isozymes are categorized into three classifications, classic, novel, and atypical, based on their structural and biochemical properties.5 The classic isozymes (cPKC) are α, β1, β2, and γ are calcium-sensitive. Novel isozymes (nPKC) are δ, ε, η, and θ are calcium-independent. The atypical (aPKC) isozymes are ξ and ι/λ. It is known that both cPKCs and nPKCs are activated by the lipid second messenger diacylglycerol (DAG).4 However, it is important to recognize that the role and the regulation

PKC regulation in prostate cancer

Phorbol ester activation of PKC triggers apoptosis in prostate cancer cells.37 Stimulation of PKC by phorbol 12-myristate 13-acetate (PMA) activates ERK1/2, p38 MAPK, and JNK in LNCaP cells.38 When Ras signaling is up-regulated, PKC inhibitors can induce apoptosis in normal prostate epithelial and cancer cells.39 This also suggests that Akt but not MAPK, is responsible for the regulation of apoptosis triggered by PKC down-regulation in both LNCaP and PC3 cell lines. Activation of JNK1 and Akt,

PKC regulation in breast cancer

Over-expression of PKC has been reported in malignant breast tissue and breast cancer cell lines.44 Earlier studies have suggested a potential role of PKC in cell development and proliferation in breast cancer.45 PKC was thought to be responsible for the increased migration of MDA-MB-231 cells.46 One report suggested that proliferation of human breast cancer cells is independent of PKC-α.47 However, the role of PKC isozymes in breast cancer remains unclear.

PKC-β may be promoter of cell growth

PKC regulation in colon cancer

As in other cell types, PKC plays a significant role in human colon cancer cells. Activation and inhibition of PKC within various colon cancer cell lines may produce conflicting effects. For instance, PKC-δ inhibitor Rottlerin inhibits cell division and proliferation of colon cancer SW1116 cells, most probably linking PKC-δ with promotion of cell division and proliferation.52 Conversely, one study measured the effects of PKC-δ knock-down using PKC-δ specific siRNA oligonucleotides and showed

PKC regulation in pancreatic cancer

PKC-α, PKC-β, and PKC-δ are increased and activated in pancreatic cancer compared to normal pancreatic tissue.27 In pancreatic cancer cell lines, inhibition of PKC could sensitize cells to the pro-apoptotic effects of the chemotherapeutic agent like gemcitabine.27 PKC-δ has also been linked to the inhibitory role in cell autophagy, suppressing the catabolic process, in pancreatic cancer.58

Another study explored the role of PKC inhibitors as potential therapies for pancreatic cancer. PKC 412, a

PKC regulation in hepatocellular cancer

While it is commonly accepted that the PKC protein family plays a central role in hepatocellular cancer (HCC) development, the specifics are still being determined. PKC-α, PKC-δ, and PKC-ι have been found to be over-expressed in human HCC cell lines.60 The focus of PKC research in HCC has predominantly been on PKC-α. Its expression is significantly increased in cancerous tissue and is correlated with tumor size and TNM stage. In addition, over-expression of the mRNA of this isozyme has been

PKC regulation in kidney cancer

The recent surge of investigations on PKC in cancer cells is particularly beneficial for renal cell carcinoma (RCC) research. Renal cell carcinoma is typically resistant to basic chemotherapy and radiation therapy,65 and thus novel methods have been sought. PKC interacts directly and indirectly with a wide variety of factors and signals in kidney cancer development and progression. Generally speaking, PKC promotes invasion of RCC, as its generalized inhibitors have been linked with reduced

Protein kinase C inhibitors

The following section summarizes the state-of-knowledge in the development and application of PKC inhibitors. Several classes of PKC inhibitors are at different levels of development in the clinic. First of all, we will discuss the development of small molecule inhibitors of PKC. This class of agents is ATP competitive inhibitors that bind to the kinase domain of the PKC isozymes. These agents have variable level of specificity for PKC isozymes. The agents in this class that are in clinical

Conclusion and perspective

Here in this short review article, we have provided succinct information as to the state of our knowledge on the role of PKC in human health and diseases. Emerging evidence clearly suggest that PKC isozymes plays critical roles in signal transduction that are involved in the regulation of cellular proliferation, apoptosis, and angiogenesis. Therefore it is believed that specific targeting of PKC isozymes could indeed be useful for the treatment of human cancers. Moreover, emerging evidence also

Conflict of interest statement

All the authors declare no competing conflict of interest.

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