Abstract
Among androgen-regulated genes, soluble guanylyl cyclase α1 (sGCα1) is significant in promoting the survival and growth of prostate cancer cells and does so independent of nitric oxide (NO) signaling. Peptides were designed targeting sGCα1 to block its pro-cancer functions and one peptide is discussed here. Peptide B-8R killed both androgen-dependent and androgen-independent prostate cancer cells that expressed sGCα1, but not cells that do not express this gene. Peptide B-8R induced apoptosis of prostate cancer cells. Importantly, Peptide B-8R does not affect nor its cytotoxicity depend on NO signaling, despite the fact that it associates with sGCα1, which dimerizes with sGCβ1 to form the sGC enzyme. Just as with a previously studied Peptide A-8R, Peptide B-8R induced elevated levels of reactive oxygen species (ROS) in prostate cancer cells, but using a ROS-sequestering agent showed that ROS was not responsible the cytotoxic activity of Peptide B-8R. Interestingly, Peptide B-8R induced elevated levels of p53 and phosphorylated p38, but neither of these changes is the cause of the peptide’s cytotoxicity. Additional drugs were used to alter levels of iron levels in cells and these studies showed that Peptide B-8R activity does not depend on Ferroptosis. Thus, future work will be directed at defining the mechanism of cytotoxic action of Peptide B-8R against prostate cancer cells.
Highlights
Because of the importance of androgen and the Androgen Receptor (AR) in both development and progression of prostate cancer [1, 2], existing therapy for this disease focuses on androgen deprivation or anti-androgen therapy[3]
For androgen (R1881) treatment, LNCaP cells were grown in medium containing 2% FBS extracted with dextran-coated charcoal (DCC). 48 hrs later, ethanol or 1 nM R1881 was added to the cells
Peptide B-8R is more potent in killing LNCaP cells than is Enzalutamide (S2A Fig), which together with the data on MR49F cells strongly suggest that Peptide B-8R may be more effective at treating castration-resistant prostate cancer (CRPC) than Enzalutamide
Summary
Because of the importance of androgen and the Androgen Receptor (AR) in both development and progression of prostate cancer [1, 2], existing therapy for this disease focuses on androgen deprivation or anti-androgen therapy[3]. More recent findings have led to the development new drugs to treat CRPC, such as the “second generation” anti-androgen Enzalutamide [5] and Abiraterone that targets androgen synthesis [6]. These drugs have shown limited efficacy in treating CRPC, providing patients only a few months of added survival time [7]. This finding necessitates the identification of new targets that can lead to new therapies.
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