Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and Cyclin E overexpression in ovarian cancer

Abstract

We show that atypical PKCiota, which plays a critical role in the establishment and maintenance of epithelial cell polarity, is genomically amplified and overexpressed in serous epithelial ovarian cancers. Furthermore, PKCiota protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKCiota DNA copy number is associated with decreased progression-free survival in serous epithelial ovarian cancers. In a Drosophila in vivo epithelial tissue model, overexpression of persistently active atypical PKC results in defects in apical-basal polarity, increased Cyclin E protein expression, and increased proliferation. Similar to the Drosophila model, increased PKCiota proteins levels are associated with increased Cyclin E protein expression and proliferation in ovarian cancers. In nonserous ovarian cancers, increased PKCiota protein levels, particularly in the presence of Cyclin E, are associated with markedly decreased overall survival. These results implicate PKCiota as a potential oncogene in ovarian cancer regulating epithelial cell polarity and proliferation and suggest that PKCiota is a novel target for therapy.

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

“…Translocation of activated PKCε to the membrane upon TPA treatment has been shown in other studies [42,55] and alteration of TJs by translocation of PKCε has been shown previously in epithelial cells [42]. 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].…”

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…Subsequent interaction of PAR1 with 14-3-3 dissociates PAR1 from the plasma membrane, thereby preventing the distribution of PAR1 to the apical membrane domain. Gene amplification and elevated activity of aPKC, which downregulates PAR1 functions, have also been reported in ovarian, lung and colon carcinomas (Murray et al, 2004;Eder et al, 2005;Regala et al, 2005).…”

The epithelial polarity program: machineries involved and their hijacking by cancer

“…Gene amplification and elevated constitutive activity of aPKC has been correlated with poor prognosis in ovarian, lung and colon cancer, suggesting that this protein may behave as an oncogene (Murray et al, 2004;Eder et al, 2005;Regala et al, 2005a, b). Tumors with elevated levels of aPKC display loss of polarity, in agreement with the known role of this kinase in regulating epithelial polarity at normal expression levels.…”