Activation of Rac1 Is Closely Related to Androgen-Independent Cell Proliferation of Prostate Cancer Cells Both in Vitro and in Vivo

Abstract

We and others previously showed that signaling through cSrc or atypical protein kinase C (aPKC) pathway regulates the proliferation of prostate cancer cells and is associated with their progression to castrate-resistance in vivo. However, the interrelation of these two kinases has been largely unexplored. In the present study, we show that androgen-induced activation of cSrc regulates the activity of aPKC through the small molecular weight G protein Rac1 in androgen-dependent LNCaP cells. Knockdown of cSrc in those cells reduces the phosphorylation of aPKC and the abundance of activated form of Rac1. Additionally, the treatment of those cells with Rac1 inhibitor repressed cell cycle progression at G(1)/S transition. In fact, forced expression of a constitutively active Rac1 mutant in LNCaP cells promoted cell proliferation under androgen-depleted conditions both in vitro and in vivo. Moreover, LNCaP C4-2 and AILNCaP cells, the syngeneic androgen-independent sublines from LNCaP cells, harbored abundant Rac1-GTP. Importantly, the inhibition of Rac1 suppressed cell proliferation and induced apoptotic cell death in all prostate cancer cell lines tested irrespective of their androgen-dependence. In immunohistochemical evaluation of tumor specimens from prostate cancer patients, Rac1 pathway appeared to be activated in the majority of castrate-resistant diseases. Collectively, our present results both in vitro and in vivo highly implicate that Rac1 can be a potential therapeutic target for patients with advanced prostate cancer, especially those with castrate-resistant status.

Rac1-Dependent Lamellipodial Motility in Prostate Cancer PC-3 Cells Revealed by Optogenetic Control of Rac1 Activity

“…Moreover, castration-resistant prostate cancer cells, which have a high malignant potential associated with invasion and metastasis, overexpress Rac1 [31]. These findings suggest that Rac1 overexpression affects the progression of prostate cancer.…”

P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer

“…Also, activation of Rac1 is associated with aggressive prostate cancer (18) and Rac1 −/− mice exhibit impaired ERK activation and regression of hematopoietic stem cells (19). Indeed, we found that resistant cell lines exhibit robust Rac1 activation compared to sensitive cells (Figure 3A).…”

The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic

“…Rac signaling is activated in castrate-resistant human tumors, and forced expression of active Rac1 in prostate cancer cells promotes both androgen-independent cell growth and a survival response (27). More recently, the Rac pathway was identified as a critical player in resistance to anti-VEGF (bevacizumab) and anti-VEGFR (sunitinib) therapy.…”