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Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21CIP1 levels in androgen-independent human prostate cancer cells

Oncogene volume 23, pages 5513–5522 (2004)Cite this article

Abstract

Abnormally suppressed levels of cyclin-dependent kinase inhibitors (CKIs) are associated with aggressive androgen-independent prostate cancer and contribute to uncontrolled proliferation. The androgen-independent human prostate cancer cell lines, LNCaP-104R1, ALVA31 and PC-3, express low levels of the CKI, p21CIP1, compared to the less-malignant, androgen-dependent LNCaP cells. We investigated the mechanism underlying this suppression by examining the role of Rho GTPases, signaling proteins that play important roles in cell cycle progression, at least in part through regulation of CKIs. Inhibition of Rac1 induced p21 expression in androgen-independent lines but had no effect on the higher p21 levels characteristic of LNCaP cells. This induction of p21 was functionally significant as evidenced by inhibition of cyclin-dependent kinase 2 activity and decreased cell proliferation. Conversely, overexpression of constitutively active Rac1 suppressed the higher p21 levels seen in LNCaP cells. Thus, Rac1 activity is both necessary and sufficient for suppression of p21 in prostate cancer cells. Furthermore, Rac1 activity was significantly higher in all three androgen-independent cell lines compared to LNCaP cells. Thus in three models of aggressive human prostate cancer, hyperactivity of Rac1 corresponds to suppressed levels of p21. These results are unique in describing a role for Rac1 in p21 regulation and may implicate the Rac1 signaling pathway as a potential therapeutic target for controlling prostate cancer cell growth following progression to androgen independence.

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Acknowledgements

This work was supported by a pre-doctoral fellowship from Pharmaceutical Research and Manufacturers of America Foundation (SKK) and grants from the Pfeiffer Research Foundation (SKK), NIH CA87668 (CFW) and US Department of Defense (DAMD17-02-1-0094) (KLB). We thank Jim Phillips (UMSM Flow Cytometry Core) for his assistance with FACS analyses.

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Authors and Affiliations

  1. Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, 1600 NW 10th Ave., Miami, 33136, FL, USA

    Selena Knight-Krajewski, Leah S Lyons, Joanne M Faysal, Eddy S Yang & Kerry L Burnstein

  2. Department of Medicine, University of Miami School of Medicine, 1600 NW 10th Ave., Miami, 33136, FL, USA

    Catherine F Welsh & YunQi Liu

  3. Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, 1600 NW 10th Ave., Miami, 33136, FL, USA

    Catherine F Welsh & Kerry L Burnstein

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  1. Selena Knight-Krajewski
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Correspondence to Kerry L Burnstein.

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Knight-Krajewski, S., Welsh, C., Liu, Y. et al. Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21CIP1 levels in androgen-independent human prostate cancer cells. Oncogene 23, 5513–5522 (2004). https://doi.org/10.1038/sj.onc.1207708

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