Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells

• Published in: Cancer letters 2017-11, Vol.408, p.73-81
• Main Authors: Datta, Amrita, Kim, Hogyoung, Lal, Madhu, McGee, Lauren, Johnson, Adedoyin, Moustafa, Ahmed A., Jones, Jennifer C., Mondal, Debasis, Ferrer, Marc, Abdel-Mageed, Asim B.
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Biosynthesis; Cancer therapies; Castration; Cell Proliferation - drug effects; Deoxyribonucleic acid; DNA; Drug delivery; Enzyme Inhibitors - pharmacology; Exosome biogenesis and secretion; Exosomes; Exosomes - drug effects; Exosomes - metabolism; Extracellular signal-regulated kinase; Flow cytometry; Gene Expression Regulation, Neoplastic - drug effects; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - genetics; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - metabolism; hnRNP H1; Humans; Inhibition; Integration; Kinases; Laboratories; Male; Manumycin A; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Penicillin; Polyenes - pharmacology; Polyunsaturated Alkamides - pharmacology; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Proteins; raf Kinases - genetics; raf Kinases - metabolism; Raf protein; ras Proteins - genetics; ras Proteins - metabolism; Ras signaling; Secretion; Signal Transduction; Splicing factors; Stem cells; Tumor Cells, Cultured
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.08.020

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. •There are no known approved drugs targeting exosome biogenesis and secretion by castration-resistant prostate cancer (CRPC) cells.•MA suppresses exosome biogenesis and secretion via inhibition of Ras/Raf/MEK/ERK1/2 signaling in CRPC cells.•The Ras-dependent MA suppression of exosome biogenesis and secretion is partly mediated via an ERK-dependent inhibition of hnRNP H1 in CRPC cells.•MA is a potential adjuvant therapeutic drug in patients presenting with CRPC.