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Cancer Lett. 2017 Nov 1;408:73-81. doi: 10.1016/j.canlet.2017.08.020. Epub 2017 Aug 24.

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.

Author information

1
Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, United States.
2
Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Cancer Institute, National Institutes of Health, Bethesda, MD 20850, United States.
3
Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, United States; Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo 11790, Egypt.
4
Molecular Immunogenetics and Vaccine Research Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20850, United States.
5
Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, United States; Department of Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, United States.
6
Department of Urology, Tulane University School of Medicine, New Orleans, LA 70112, United States; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, United States; Department of Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, United States. Electronic address: amageed@tulane.edu.

Abstract

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.

KEYWORDS:

Exosome biogenesis and secretion; Manumycin A; Prostate cancer; Ras signaling; hnRNP H1

PMID:
28844715
PMCID:
PMC5628151
DOI:
10.1016/j.canlet.2017.08.020
[Indexed for MEDLINE]
Free PMC Article

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