2. Academic Validation
  3. 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

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

  • Cancer Lett. 2017 Nov 1;408:73-81. doi: 10.1016/j.canlet.2017.08.020.
Amrita Datta 1,  Hogyoung Kim 1,  Madhu Lal 2,  Lauren McGee 2,  Adedoyin Johnson 1,  Ahmed A Moustafa 3,  Jennifer C Jones 4,  Debasis Mondal 5,  Marc Ferrer 2,  Asim B Abdel-Mageed 6
Affiliations

Affiliations

  • 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.
PMID: 28844715 DOI: 10.1016/j.canlet.2017.08.020
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.

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