manumycin and Prostatic-Neoplasms--Castration-Resistant

Emerging evidence links exosomes to cancer progression by the trafficking of oncogenic factors and neoplastic reprogramming of stem cells. This necessitates identification and integration of functionally validated exosome-targeting therapeutics into current cancer management regimens. We employed quantitative high throughput screen on two libraries to identify exosome-targeting drugs; a commercially available collection of 1280 pharmacologically active compounds and a collection of 3300 clinically approved compounds. Manumycin-A (MA), a natural microbial metabolite, was identified as an inhibitor of exosome biogenesis and secretion by castration-resistant prostate cancer (CRPC) C4-2B, but not the normal RWPE-1, cells. While no effect was observed on cell growth, MA attenuated ESCRT-0 proteins Hrs, ALIX and Rab27a and exosome biogenesis and secretion by CRPC cells. The MA inhibitory effect is primarily mediated via targeted inhibition of the Ras/Raf/ERK1/2 signaling. The Ras-dependent MA suppression of exosome biogenesis and secretion is partly mediated by ERK-dependent inhibition of the oncogenic splicing factor hnRNP H1. Our findings suggest that MA is a potential drug candidate to suppress exosome biogenesis and secretion by CRPC cells.

Topics: Apoptosis; Cell Proliferation; Enzyme Inhibitors; Exosomes; Gene Expression Regulation, Neoplastic; Heterogeneous-Nuclear Ribonucleoprotein Group F-H; Humans; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Polyenes; Polyunsaturated Alkamides; Prostatic Neoplasms, Castration-Resistant; raf Kinases; ras Proteins; Signal Transduction; Tumor Cells, Cultured