title: The marine natural product manzamine A targets vacuolar ATPases and inhibits autophagy in pancreatic cancer cells.
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.
authors.affiliation: Marine Biomedical and Biotechnology Research Program, Harbor Branch Oceanographic Institute, Florida Atlantic University, 5600 US 1 North, Fort Pierce, FL 34946, USA.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kallifatidis
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Jaeg
authors.forename: Esther A
authors.initials: EA
authors.lastname: Guzmán
authors.forename: Amy E
authors.initials: AE
authors.lastname: Wright
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017494:Proton Pumps / Q000378:metabolism; D011522:Protons; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002227:Carbazoles; C477012:MAP1LC3A protein, human; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D017494:Proton Pumps; D011522:Protons; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C078290:manzamine A; C040929:bafilomycin A1; D025262:Vacuolar Proton-Translocating ATPases
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