Elevated protein kinase C beta II is an early promotive event in colon carcinogenesis

Protein kinase C (PKC) has been implicated in colon carcinogenesis in human s and in rodent models. However, little is known about the specific role of individual PKC isozymes in this process. We recently demonstrated that ele vated expression of PKC PII in the coIonic epithelium induces hyperprolifer ation in vivo (N. R, Murray ef at, J, Cell Biol,, 145: 699-711, 1999), Beca use hyperproliferation is a major risk factor for colon cancer, we assessed whether specific alterations in PKC pn expression occur during azoxymethan e-induced colon carcinogenesis in mice. An increase in PKC PII expression w as observed in preneoplastic lesions (aberrant crypt foci, 3.7-fold) compar ed with saline-treated animals, and in colon tumors (7.8-fold; P = 0.011) c ompared with uninvolved colonic epithelium, In contrast, PKC cu and PKC PI (a splicing variant of PKC PII) expression was slightly decreased in aberra nt crypt foci and dramatically reduced in colon tumors. Quantitative revers e transcription-PCR analysis revealed that PRC mRNA levels do not directly correlate with PKC protein levels, indicating that PKC isozyme expression i s likely regulated at the posttranstriptional/translational level. Finally, transgenic mice expressing elevated PKC PII in the colonic epithelium exhi bit a trend toward increased colon tumor formation after exposure to azoxym ethane. Taken together, our results demonstrate that elevated expression of PKC beta II is an important early, promotive event that plays a role in co lon cancer development.