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

Abstract

Abnormally suppressed levels of cyclin-dependent kinase inhibitors (CKIs) are associated with aggressive androgenindependent 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, p21 CIP1 , 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.

c-Myc Suppresses p21WAF1/CIP1 Expression during Estrogen Signaling and Antiestrogen Resistance in Human Breast Cancer Cells

“…Together, our results and these reports strongly support a central role for CDK inhibitors and their direct upstream regulators in antiestrogen resistance. Levels of these CDK inhibitors are also suppressed in androgen-independent prostrate cancer cells (50,67,68), indicating that they may play a more general role in resistance to hormonal regulation.…”

Vav3-Rac1 Signaling Regulates Prostate Cancer Metastasis with Elevated Vav3 Expression Correlating with Prostate Cancer Progression and Posttreatment Recurrence

“…Accumulating evidence indicates the important role of Rac1-mediated signaling in malignant transformation (35,36). Elevated expression of Rac1 in prostate cancer (37) and its suppression of the cyclin-dependent kinase inhibitor p21 (CIP1) in prostate cancer cells (38) suggest the involvement of Rac1 in prostate cancer progression. Several Rac-specific GEFs have been linked to tumor progression, such as Tiam1 (39) and DOCK3 (40).…”

Lost in Transcription: p21 Repression, Mechanisms, and Consequences

“…However, the mechanism of this repression has not yet been established. Similarly, although it is known that GTPases Rac1 and RhoA can repress p21 transcription (73,74), the functional elements on the p21 promoter responsible for this repression remain unidentified. Regardless of the mechanism, the result of p21 repression in the majority of the above cases has always been cell cycle progression.…”