A peptide against soluble guanylyl cyclase ?1: a new approach to treating prostate cancer.

ABSTRACT: Among the many identified androgen-regulated genes, sGC?1 (soluble guanylyl cyclase ?1) appears to play a pivotal role in mediating the pro-cancer effects of androgens and androgen receptor. The classical role for sGC?1 is to heterodimerize with the sGC?1 subunit, forming sGC, the enzyme that mediates nitric oxide signaling by catalyzing the synthesis of cyclic guanosine monophosphate. Our published data show that sGC?1 can drive prostate cancer cell proliferation independent of hormone and provide cancer cells a pro-survival function, via a novel mechanism for p53 inhibition, both of which are independent of sGC?1, NO, and cGMP. All of these properties make sGC?1 an important novel target for prostate cancer therapy. Thus, peptides were designed targeting sGC?1 with the aim of disrupting this protein's pro-cancer activities. One peptide (A-8R) was determined to be strongly cytotoxic to prostate cancer cells, rapidly inducing apoptosis. Cytotoxicity was observed in both hormone-dependent and, significantly, hormone-refractory prostate cancer cells, opening the possibility that this peptide can be used to treat the usually lethal castration-resistant prostate cancer. In mouse xenograft studies, Peptide A-8R was able to stop tumor growth of not only hormone-dependent cells, but most importantly from hormone-independent cells. In addition, the mechanism of Peptide A cytotoxicity is generation of reactive oxygen species, which recently have been recognized as a major mode of action of important cancer drugs. Thus, this paper provides strong evidence that targeting an important AR-regulated gene is a new paradigm for effective prostate cancer therapy.

SUBMITTER: Gao S 

PROVIDER: S-EPMC3664642 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature