1. ¹Department of Dermatology, University of Colorado Health Science Center at Fitzsimons, Aurora, Colorado, USA
2. ²Department of Chemistry and Biochemistry, University of Colorado at Boulder, Colorado, USA
3. ³Department of Veterans Affairs Medical Center, Dermatology Section, Denver, Colorado, USA

Correspondence: Assistant Professor Yiqun G. Shellman, UCDHSC at Fitzsimons, Dermatology Department, Mail Stop #8127, PO Box 6511, Aurora, Colorado 80045, USA. E-mail: yiqun.shellman@uchsc.edu

Received 16 August 2005; Revised 12 December 2005; Accepted 2 January 2006; Published online 9 February 2006.

Abstract

Overexpression of the small GTPase, RhoC, in various human cancers has been correlated with high metastatic ability and poor prognosis. Rho-kinase (ROCK) is an important effector of Rho GTPases. The oncogenic serine/threonine kinase Akt (also known as PKB) is a downstream effector of phosphatidylinositol-3 kinase (PI3K). Akt activation contributes to the neoplastic phenotype by promoting cell cycle progression, increasing antiapoptotic functions, and enhancing tumor cell invasion. Rho signaling via ROCK has been previously shown either to activate or to downregulate PI3K/Akt. Using a human radial growth phase melanoma cell line, WM35, we have established stable transfectants that overexpress RhoC (called WM35RhoC). We found that overexpression of RhoC increased phosphorylated-Akt (Ser473/474/472, pAkt) expression and promoted cell invasion. Inhibition of RhoC with C3 transferase downregulated pAkt expression and decreased cell invasion in these cells. In addition, inhibition of PI3K, Akt, or ROCK partially decreased invasion. Further, inhibition of PI3K but not ROCK decreased the pAkt level. These results suggest that RhoC promotes invasion in part via activation of a PI3K/Akt pathway, in a manner independent of ROCK signaling. We propose that RhoC promotes melanoma progression via separate mechanisms that regulate the PI3K/Akt pathway and the ROCK signaling pathway.