Regulation of Prostate Cancer Cell Survival by Protein Kinase C∈ Involves Bad Phosphorylation and Modulation of the TNFα/JNK Pathway

Abstract

Protein kinase C⑀ (PKC⑀), a diacyglycerol-and phorbol esterresponsive serine-threonine kinase, has been implicated in mitogenic and survival control, and it is markedly overexpressed in human tumors, including in prostate cancer. Although prostate cancer cells undergo apoptosis in response to phorbol ester stimulation via PKC␦-mediated release of death factors, the involvement of PKC⑀ in this response is not known. PKC⑀ depletion by RNAi Protein kinase C (PKC), 3 a family of serine-threonine kinases that comprises the classical (cPKCs ␣, ␤, and ␥), novel (nPKCs ␦, ⑀, , and ), and atypical (aPKCs and ) PKCs, is a key signaling component of growth factor and cytokine pathways. Despite their structural similarities, PKC isozymes have unique modes of regulation as well as differential patterns of cell and tissue expression (1, 2). Only cPKCs and nPKCs are regulated by phorbol esters and diacylglycerol, a lipid second messenger generated upon activation of G protein-coupled receptors and tyrosine kinases (1-3). Phorbol esters are capable of promoting opposite responses in different cell types, such as mitogenesis/ survival versus growth arrest/apoptosis. This paradigm of functional diversity is exemplified by the nPKCs: whereas in most cases PKC⑀ acts as a mitogenic or antiapoptotic kinase, activation of PKC␦ inhibits proliferation or triggers an apoptotic response (4 -8). PKC⑀ can signal to mitogenesis via Raf/MEK/ ERK and cyclin D1 induction (9, 10) or can even transform cells (4, 6, 11). In addition, PKC⑀ has been linked to cell survival through the activation of Akt and Bax (12,13).Tumor cells display in many cases an altered balance in PKC isozyme expression, potentially reflecting the involvement of PKCs in the etiology and progression of cancer. Most notably, many cancer cells show marked up-regulation of PKC⑀. PKC⑀ is elevated in prostate cancer, particularly in high grade tumors, and is implicated in prostate tumor progression and the transition to androgen-independence (14 -17). The functional complexity of PKC in prostate cancer cells is nonetheless highlighted by the fact that phorbol esters promote an apoptotic response in androgen-dependent prostate cancer cells (18,19). Previous work from our laboratory and others established that PKC␦ is the major mediator of the death effect of PMA in LNCaP cells (19 -21). In this context, the role of PKC⑀ remains controversial, as unlike in other cell types, PKC⑀ was found to be either dispensable for prostate cancer cell survival or even contribute to the proapoptotic effects of PKC activators (22-24). Given our limited understanding of the mechanistic insights of PKC-driven responses in prostate cancer cells, additional studies would be required to ascertain the specific contribution of PKC isozymes to this paradox.We have recently demonstrated that PKC␦-mediated prostate cancer cell death involves the activation of an apoptotic autocrine loop through the release of death factors (primarily TNF␣), and the subsequent activation of the extrinsic apoptotic cascade ...

Bryostatin 1 Inhibits Phorbol Ester-Induced Apoptosis in Prostate Cancer Cells by Differentially Modulating Protein Kinase C (PKC) δ Translocation and Preventing PKCδ-Mediated Release of Tumor Necrosis Factor-α

“…3B). A slightly higher apoptotic effect of PMA was observed in PKC-depleted LNCaP cells, consistent with its prosurvival effect in this model (McJilton et al, 2003;Meshki et al, 2010). Most importantly, only PKC␦ depletion could significantly impair TNF␣ release by the phorbol ester, whereas depletion of either PKC␣ or PKC failed to block secretion of the death factor (Fig.…”

Activation of Nuclear Factor κB (NF-κB) in Prostate Cancer Is Mediated by Protein Kinase C ϵ (PKCϵ)

“…Expression of PKC⑀ was readily detected 24 h after infection and remained stable for several days (Ref. 24) and data not shown).…”

“…Studies from several laboratories, including ours, revealed that PKC␦ generally acts as a negative regulator of proliferation and/or mediates apoptotic responses, whereas PKC⑀ is a prosurvival and mitogenic kinase (19 -22). In prostate cancer cells, activation of PKC⑀ accelerates G 1 /S transition, mediates survival through Bad-dependent and Bad-independent mechanisms, and confers androgen independence (23)(24)(25). Most interestingly, PKC⑀ emerged as a potential oncogene and cancer biomarker and it is up-regulated not only in prostate cancer but also in several other epithelial cancers including lung, breast, and thyroid cancer (19,26,27).…”

Protein Kinase C (PKC) Isozymes and Cancer

“…Furthermore, PKC -mediated antiapoptotic properties are obtained through the effects on multiple signaling pathways, such as phosphorylation and inactivation of proapoptotic Bad [444], inhibition of TNF -induced JNK activation [444], inhibition of I B phosphorylation and degradation [445], and interaction of PKC with proapoptotic Bax, all of which result in the neutralization of apoptotic signals [446]. Furthermore, PKC increases P-gp-mediated drug resistance [447].…”