Rhoa-dependent murine prostate cancer cell proliferation and apoptosis: Role of protein kinase cζ

• Published in: Cancer research (Chicago, Ill.) Vol. 62; no. 9; pp. 2630 - 2636
• Main Authors: GHOSH, Paramita M, BEDOLLA, Roble, MIKHAILOVA, Margharita, KREISBERG, Jeffrey I
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2002
• Subjects: Biological and medical sciences; Cell cycle, cell proliferation; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology; Cell proliferation; Protein kinase C; Prostate disease; Transgenic animal; Esterases; Signal transduction; Established cell line; Mechanism of action; Male genital diseases; Tumor cell; Urinary system disease; Enzyme; Triphosphoric monoester hydrolases; Transferases; Rodentia; dGTPase; Malignant tumor; Gene expression; In vitro; Vertebrata; Mammalia; Mouse; Cell death; Animal; Hydrolases; Prostate; Apoptosis
• ISSN: 0008-5472; 1538-7445

We previously showed that RhoA played an important role in the proliferation of murine Weprostate cancer (TRAMP) cells (P. M. Ghosh et al., Oncogene, 18: 4120-4130, 1999). Untransfected TRAMP cells as well as those expressing constitutively active RhoA (Q63L) mutant protein (Q63L cells) were highly proliferative. In contrast, TRAMP cells expressing dominant-negative RhoA (T19N) mutant protein (T19N cells) were slow growing. In this study, we showed, in addition, that T19N cells displayed reduced rates of apoptotic cell death in response to serum deprivation, compared with TRAMP and Q63L cells, and we studied the mechanisms of the effects of RhoA on TRAMP cell proliferation and apoptosis. Both proliferation and apoptosis of TRAMP and Q63L cells were dependent on the activation of phosphatidylinositol 3-kinase (PI3K). The ubiquitous mitogen-activated Ser/Thr kinase, p70S6 kinase, a downstream effector of PI3K, was overexpressed in TRAMP and Q63L cells. Another PI3K effector, the cell survival protein Akt, displayed increased activity in T19N cells, which did not express active RhoA, compared with TRAMP and Q63L cells. The atypical protein kinase C (PKC) isoform PKC zeta , which is downstream of PI3K, was activated in cells expressing active RhoA. In addition, expression of constitutively activated PKC zeta in TRAMP cells enhanced proliferation and p70S6 kinase phosphorylation, whereas the inhibition of PKC zeta activation resulted in activation of Akt and enhanced cell survival. Thus, the effects of RhoA on TRAMP cell proliferation and apoptosis may be mediated by PKC zeta .