title: Papuamine causes autophagy following the reduction of cell survival through mitochondrial damage and JNK activation in MCF-7 human breast cancer cells.
abstract: We previously reported that extracts of an Indonesian marine sponge Haliclona sp. showed potent cytotoxicity and the induction of apoptosis against human solid cancer cell lines. In this study, we examine the cytotoxic mechanism of the major chemical compound, papuamine, on MCF-7 human breast cancer cells. Papuamine at 5 µM did not show significant cytotoxic effects after incubation for 24 h, but autophagosome vesicular formation was apparent. At 10 µM of papuamine, significant reduction in cell survival was observed at 12 h, and increases in autophagy at this concentration were time-dependent and apparent before the appearance of cytotoxic effects. Both the release of cytochrome c to the cytosol and increase in Bax in the mitochondrial fraction were found to be concentration-dependent. Moreover, mitochondrial membrane potential shows concentration- and time-dependent decreases with exposure to papuamine. The release of cytochrome c has been shown to be accompanied by an increase in JNK activation. 3-Methyladenine (MA), a classical autophagy inhibitor showed increased JNK activation by exposure to papuamine. In conclusion, our results indicate that papuamine causes earlier onset autophagy and delayed reduction of cell survival through mitochondrial damage and JNK activation in MCF-7 cells.
authors.affiliation: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Syu-Ichi
authors.initials: S
authors.lastname: Kanno
authors.forename: Shin
authors.initials: S
authors.lastname: Yomogida
authors.forename: Ayako
authors.initials: A
authors.lastname: Tomizawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Ukai
authors.forename: Remy E P
authors.initials: RE
authors.lastname: Mangindaan
authors.forename: Michio
authors.initials: M
authors.lastname: Namikoshi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ishikawa
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000470:Alkaloids; D019253:Proto-Oncogene Proteins c-bcl-2; C585611:papuamine; D045304:Cytochromes c; D048670:MAP Kinase Kinase 4
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