The marine natural product manzamine a targets vacuolar atpases and inhibits autophagy in pancreatic cancer cells

Georgios Kallifatidis, Dominic Hoepfner, Tiphaine Jaeg, Esther A. Guzmán, Amy E. Wright

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Manzamine A, a member of the manzamine alkaloids, was originally isolated from marine sponges of the genus Haliclona. It was recently shown to have activity against pancreatic cancer cells, but the precise mechanism of action remained unclear. To further our understanding of the mechanism of action of manzamine A, chemogenomic profiling in the yeast S. cerevisiae was performed, suggesting that manzamine A is an uncoupler of vacuolar ATPases. Fluorescence microscopy confirmed this effect on yeast vacuoles, where manzamine A produced a phenotype very similar to that of the established v-ATPase inhibitor bafilomycin A1. In pancreatic cancer cells, 10 μM manzamine A affected vacuolar ATPase activity and significantly increased the level of autophagosome marker LC3-II and p62/SQSTM1 as observed by western blot analysis. Treatment with manzamine A in combination with bafilomycin A1 (inhibitor of autophagosome-lysosome fusion) did not change the levels of LC3-II when compared to cells treated with bafilomycin A1 alone, suggesting that manzamine A is a potential inhibitor of autophagy by preventing autophagosome turnover. As autophagy is essential for pancreatic tumor growth, blocking this pathway with manzamine A suggests a promising strategy for the treatment of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)3500-3516
Number of pages17
JournalMarine Drugs
Volume11
Issue number9
DOIs
StatePublished - Sep 1 2013

Fingerprint

Vacuolar Proton-Translocating ATPases
Autophagy
Biological Products
Pancreatic Neoplasms
Haliclona
Yeasts
manzamine A
Porifera
Vacuoles
Lysosomes
Fluorescence Microscopy
Alkaloids
Saccharomyces cerevisiae
Adenosine Triphosphatases
Western Blotting
Phenotype

Keywords

  • Autophagy
  • Lysosome
  • Manzamine A
  • Pancreatic cancer
  • Vacuolar ATPase

ASJC Scopus subject areas

  • Drug Discovery

Cite this

The marine natural product manzamine a targets vacuolar atpases and inhibits autophagy in pancreatic cancer cells. / Kallifatidis, Georgios; Hoepfner, Dominic; Jaeg, Tiphaine; Guzmán, Esther A.; Wright, Amy E.

In: Marine Drugs, Vol. 11, No. 9, 01.09.2013, p. 3500-3516.

Research output: Contribution to journalArticle

Kallifatidis, Georgios ; Hoepfner, Dominic ; Jaeg, Tiphaine ; Guzmán, Esther A. ; Wright, Amy E. / The marine natural product manzamine a targets vacuolar atpases and inhibits autophagy in pancreatic cancer cells. In: Marine Drugs. 2013 ; Vol. 11, No. 9. pp. 3500-3516.
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