A tale of three PKCs

The concept that classical and novel PKCs exert divergent outcomes in cancer has been long appreciated (reviewed in ref. 1). The PKC family of serine-threonine kinases is comprised of ten related members, including “classical” (cPCKs α, β, and γ), “atypical” (aPKCs ι/λ and ζ), and “novel” (nPKC δ, ε, η, and µ) subclasses according to structural motifs, calcium requirement and mechanisms of activation. The individual PKCs regulate diverse and sometimes opposing cellular processes such as proliferation, apoptosis, migration/motility, differentiation and, most notably, are thought to play unique roles in cancer development and progression. The potential impact of PKCs on tumor development was realized almost three decades ago when PKCs were identified as intracellular receptors for tumor-inducing phorbol esters.² These initial discoveries ignited a season of discovery for discerning the overall influence of PKCs in tumorigenesis and tumor progression (reviewed in ref. 3).

Elegant in vitro and in vivo studies revealed that PKC functions in cancer are distinct among the kinases and show tissue specificity. For example, while PKCα does not alter skin cancer development in animal models, this isoform was identified as a critical mediator of proliferation in squamous cell carcinomas of the head and neck and as a marker of poor clinical outcome in this disease.^4,5 Similarly conflicting data has been observed with PKCδ; this isoform has been shown to be anti-proliferative in animal models of skin cancer and exerts anti-tumor properties in rodent colon epithelia, but evidence supports a pro-survival role for PKCδ in cells derived from lung or breast cancer (reviewed in ref. 6). The divergent and context-specific functions of PKCs in cancer illuminate the urgent need to consider the tumor-specific and clinically relevant effects of PKC alterations using in vivo models.

In a recent study by Benavides, Kazanietz and colleagues,⁷ the impact of three distinct PKC isoforms was assessed using novel, prostate-specific transgenic models. Transgene expression was confined to the epithelial compartment, and animals homozygous for transgenic PKCα, PKCδ or PKCε expression were analyzed for histological changes after 12 mo. Notably, significant epithelial hyperplasia was observed in PKCε but not PKCα or PKCδ models, and similar results were observed in vitro upon individual expression of the three isoforms into human prostatic epithelial cells immortalized with viral oncoproteins. Combined, these findings reveal specificity of PKCε for inducing pro-proliferative effects in prostatic epithelia.

While no evidence of neoplastic lesion formation was observed in the PKCε animals, dysplastic changes characteristic of mPIN (murine prostatic intraepithelial neoplasia) developed in multiple lobes of the prostate. Subsequent investigation revealed that mPIN lesions in the PKCε-expressing compartments displayed concomitant hyperactivation of AKT. It will be of significant interest to determine if this event is requisite for PKCε-mediated phenotypes, as prostate-specific expression of AKT also drives formation of mPIN lesions that do not progress to neoplasia, and excessive AKT activation is thought to play a major role in human disease.⁸ In addition, a subset of PKCε overexpressing mPIN lesions exhibited elevation in total and activated Stat3. Given the putative oncogenic functions of Stat3 in human disease and the impact of Stat3 activation on tumor phenotypes,⁹ it is enticing to speculate that PKCε-positive tumors may show altered clinical behavior. Accordingly, the present study showed that PKCε expression conferred moderate resistance to castration. A caveat of the prostate-specific expression model is that the transgene is under control of an androgen-

dependent promoter (and is therefore attenuated in response to castration); nonetheless, the PKCε-transgenic epithelia showed a reduced apoptotic index after castration as compared with the PKCα or PKCδ transgenics.

Taken together, this tale of three PKCs defines the epsilon isoform as a driver of pre-neoplastic changes in the prostate, and provides an important new model with which to assess mechanism (including the role of AKT and Stat3), discern specificity of function, identify cooperative oncogenic factors and determine impact on therapeutic intervention. In this age of wisdom, wherein inhibitors of PKCs are both in development and in clinical trial, the present findings provide the impetus for developing PKCε as a putative new target for human prostate cancer.

Benavides F, Blando J, Perez CJ, Garg R, Conti CJ, DiGiovanni J, et al. Transgenic overexpression of PKCε in the mouse prostate induces preneoplastic lesions. Cell Cycle. 2011;10:268–77. doi: 10.4161/cc.10.2.14469.