Abstract
Deregulated Rho GTPases Rac1 and Cdc42 have been discovered in various tumors, including prostate and Rac protein expression significantly increases in prostate cancer. The Rac and Cdc42 pathways promote the uncontrolled proliferation, invasion and metastatic properties of human cancer cells. We synthesized the novel compound AZA1 based on structural information of the known Rac1 inhibitor NSC23766. In the current study we investigated the effects of inhibition of these pathways by AZA1 on prostate tumorigenicity by performing preclinical studies using a xenograft mouse model of prostate cancer. In androgen-independent prostate cancer cells, AZA1 inhibited both Rac1 and Cdc42 but not RhoA GTPase activity in a dose-dependent manner and blocked cellular migration and proliferation. Cyclin D1 expression significantly decreased following Rac1/Cdc42 inhibition in prostate cancer cells. AZA1 treatment also down-regulated PAK and AKT activity in prostate cancer cells, associated with induction of the pro-apoptotic function of BAD by suppression of serine-112 phosphorylation. Daily systemic administration of AZA1 for 2 weeks reduced growth of human 22Rv1 prostate tumor xenografts in mice and improved the survival of tumor-bearing animals significantly. These data suggest a role of AZA1 in blocking Rac1/Cdc42-dependent cell cycle progression, cancer cell migration and increase of cancer cell apoptosis involving down-regulation of the AKT and PAK signaling pathway in prostate cancer cells. We therefore propose that a small-molecule inhibitor therapy targeting Rac1/Cdc42 Rho GTPase signaling pathways may be used as a novel treatment for patients with advanced prostate cancer.
Highlights
Prostate cancer is the leading cause of cancer and second leading cause of cancer-related deaths in men [1]
The activity of Rac1 was upregulated over threefold after stimulation of 22Rv1 prostate cancer cells with epidermal growth factor (EGF) when compared to untreated cells
As no constitutively active mutant forms of Rho GTPases have been found in human tumors [4] and overexpression of Rho GTPases such as Rac1 and Cdc42 occurs in many malignancies including prostate cancer [7,35,36,37], it can be assumed that over-expression rather than Rho GTPase activation mutations is associated with tumorigenesis
Summary
Prostate cancer is the leading cause of cancer and second leading cause of cancer-related deaths in men [1]. Screening for prostate cancer has improved, 10–20% of patients will be diagnosed with locally advanced or metastatic disease while others will progress despite surgery, radiation and androgendeprivation therapy [2,3]. Advanced prostate cancer remains a significant health care problem and the identification of novel targeted therapies focusing on molecular signaling pathways are essential to improve therapeutic intervention. Rho GTPases such as Rac, Cdc and RhoA are signaling proteins that regulate cytoskeleton organization, cell cycle progression, cell survival and migration directly contributing to tumor growth and progression [4]. Deregulated Rho GTPases have been discovered in various proliferative malignancies, including prostate tumors [4] and Rac protein expression is significantly increased in prostate cancer [7]
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