Abstract
Among the many identified androgen-regulated genes, sGCα1 (soluble guanylyl cyclase α1) appears to play a pivotal role in mediating the pro-cancer effects of androgens and androgen receptor. The classical role for sGCα1 is to heterodimerize with the sGCβ1 subunit, forming sGC, the enzyme that mediates nitric oxide signaling by catalyzing the synthesis of cyclic guanosine monophosphate. Our published data show that sGCα1 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 sGCβ1, NO, and cGMP. All of these properties make sGCα1 an important novel target for prostate cancer therapy. Thus, peptides were designed targeting sGCα1 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.
Highlights
One important target tissue of androgens and androgen receptor (AR) is the prostate
We have previously shown that one important mediator of prostate cancer cell proliferation is soluble guanylyl cyclase a1 [7]. sGCa1 was originally identified as a component of sGC, a heterodimeric enzyme, consisting of sGCa1 and sGCb1 subunits, that mediates biological functions of nitric oxide (NO) [8]
To begin to address this possibility, we used these previous data showing that sGCa1 pro-cancer functions are independent of NO signaling and sGCb1 [7], [10] and that sGCb1 can relieve sGCa1-mediated repression of p53 transcriptional activity [10], suggesting that sGCb1 dimerization with sGCa1 can disrupt sGCa1 pro-cancer functions
Summary
Like the development of normal prostate, the growth and progression of prostate cancer are dependent on androgens and AR [1]. When physiological levels of androgens are replaced in a castrated rat, prostate epithelial cell proliferation is increased and apoptosis is decreased, leading to reconstitution of a normal prostate [3]. All the data accumulated far strongly suggest that androgens, through the activity of AR, regulate the rate of cellular proliferation while inhibiting the rate of cell death in the prostate [6]. Dysregulation of this balance between cell proliferation and cell death is undoubtedly critical to the development of prostate cancer
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