Protein kinase Cε and development of squamous cell carcinoma, the nonmelanoma human skin cancer

Abstract

Protein kinase C (PKC) represents a large family of phosphatidylserine (PS)-dependent serine/threonine protein kinases. At least five PKC isoforms (alpha, delta, epsilon, eta, and zeta) are expressed in epidermal keratinocytes. PKC isoforms are differentially expressed in proliferative (basal layer) and nonproliferative compartments (spinous, granular, cornified layers), which exhibit divergence in their roles in the regulation of epidermal cell proliferation, differentiation, and apoptosis. Immunocytochemical localization of PKC isoforms indicate that PKCalpha is found in the membranes of suprabasal cells in the spinous and granular layers. PKCepsilon is mostly localized in the proliferative basal layers. PKCeta is localized exclusively in the granular layer. PKCdelta is detected throughout the epidermis. PKC isozymes exhibit specificities in their signals to the development of skin cancer. PKCepsilon, a calcium-insensitive PKC isoform mediates the induction of squamous cell carcinoma (SCC) elicited either by the DMBA-TPA protocol or by repeated exposures to ultraviolet radiation (UVR). PKCepsilon overexpression, which sensitizes skin to UVR-induced carcinogenesis, suppresses UVR-induced sunburn (apoptotic) cell formation, and enhances both UVR-induced levels of TNFalpha and hyperplasia. UVR-induced sunburn cell formation is mediated by Fas/Fas-L and TNFalpha NFR1 extrinsic apoptotic pathways. The death adaptor protein termed Fas-associated death domain (FADD) is a common adaptor protein for both of these apoptotic pathways. PKCepsilon inhibits UVR-induced expression of FADD leading to the inhibition of both apoptotic pathways. It appears that PKCepsilon sensitizes skin to the development of SCC by UVR by transducting signals, which inhibit apoptosis on one hand, and enhances proliferation of preneoplastic cells on the other hand.

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

“…Various isoforms of PKC have been implicated in ovarian tumorigenesis and drug resistance [56][57][58][59][60][61][62]. Involvement of PKCε in tumor development, invasion, and metastasis have been shown in other tissues [50,[63][64][65][66][67]. However, little is known about the roles of PKCε in ovarian cancer and, in light of the results reported here, this PKC isoform certainly deserves further consideration in ovarian tumorigenesis.…”

VEGF-C and VEGF-D Blockade Inhibits Inflammatory Skin Carcinogenesis

“…Simultaneously, the transcription of TNF-a is upregulated (28) and activates the classical signs of inflammation, including redness (blood vessel dilatation) and swelling (increased blood vascular permeability), resulting in continuous recruitment of inflammatory cells to the treated skin (27). After only three applications of TPA, the skin of transgenic mice seemed less inflamed than the skin of similarly treated wild-type mice.…”

Protein kinase Cε makes the life and death decision

“…PKCε was shown to be an important mediator of squamous cell carcinogenesis [48]. Targeted overexpression of PKCε in mouse epidermis caused development of squamous cell carcinoma (SCC) following application of 7,12-dimethylbenz(a)anthracene (DMBA) and 12-Otetradecanoylphorbol-13-acetate (TPA) protocol or ultraviolet radiation (UVR).…”