Abstract 2848: SHLP6: A naturally occurring mitochondrial-derived peptide has therapeutic potential in prostate cancer

Abstract

Abstract Mitochondrial DNA (mtDNA) mutations have been demonstrated in prostate cancer, particularly at the 16S rRNA region; and abnormal mRNA transcripts from that locus have been described. We and others showed that a novel open reading frame (ORF) within the mitochondrial 16S rRNA region, encoding for a 24 AA peptide called humanin, is a potent cell-survival and metabolic factor. Hypothesizing that additional bioactive peptides may be encoded from this region we identified an additional six ORFs that encode peptides transcribed from within the 16s rRNA gene in the mtDNA, which we have named small humanin-like peptides, or SHLPs. SHLP1-5 are functionally analogous to humanin, and act as potent survival factors. Intriguingly an additional peptide, SHLP6, functions in a completely opposing manner. We demonstrate that endogenous SHLP6 is expressed in serum and in multiple tissues, including the prostate, and that its expression declines with age. In addition, the addition of exogenous SHLP6 promotes apoptosis in prostate cancer cell lines including 22RV1, LNCaP and DU145. To assess the in vivo potency of SHLP6, we treated 22RV1 xenografts in SCID mice with SHLP6 for 1 week, and observed a potent inhibition of CaP xenograft growth and angiogenesis in vivo. In addition, we show that SHLP6 expression is decreased in preliminary staining of human prostate cancer, compared with normal prostate tissue. Analysis of gene and protein expression of SHLP6 treated cells reveals modulation of cell cycle and apoptosis genes and a dramatic inhibition of VEGF expression. Importantly, treatment of prostate cells with siRNA against SHLP6 leads to a dramatic increase in VEGF expression, suggesting that endogenous SHLP6 plays a role in the regulation of VEGF levels. We therefore propose the revolutionary concept that a previously unrecognized family of peptides is produced from the mitochondria and that one of these, SHLP6, plays a key role in regulating angiogenesis, is altered in prostate cancer, and may serve as a novel therapeutic and diagnostic agent in this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2848. doi:10.1158/1538-7445.AM2011-2848