Malformin A1 promotes cell death through induction of apoptosis, necrosis and autophagy in prostate cancer cells.

PURPOSE - Malformin A1 (MA1), a cyclopentapeptide isolated from fungal origin, has been identified to induce varieties of intriguing biological activities. Here, we reported the mode of mechanism underlying MA1-mediated cytotoxicity through induction of apoptosis, necrosis and autophagy in prostate cancer (PCa) cells.

METHODS - Human PCa cells PC3 and LNCaP were treated with MA1, and cell viability, apoptosis, necrosis, mitochondrial damage, oxidative stress and autophagy were analyzed, respectively. Pharmacological inhibitors, transient transfection of plasmids and siRNAs were then used to identify the roles of oxidative stress and autophagy in MA1-triggered cell death.

RESULTS - In both PC3 and LNCaP cells, MA1 inhibited cell proliferation and triggered oxidative stress via the rapid accumulation of reactive oxygen species and a decrease in mitochondrial transmembrane potential. Mitochondrial damage by MA1 triggered caspase activation and intracellular ATP deletion, leading to apoptosis and necrosis, respectively. Meanwhile, MA1 activated autophagy as indicated by conversion of LC3BI to LC3BII and increased GFP-tagged LC3B punctate dots. Pharmacological inhibition of autophagy or knocking down LC3B attenuated MA1-mediated cell death. Excessive oxidative stress and decreased ATP stimulated AMPK/mTOR pathway, which led to induction of MA1-mediated autophagy.

CONCLUSIONS - Coaction of apoptotic, necrotic and autophagic cell death induced by mitochondrial damage defines a novel mechanism contributing to the growth suppression of MA1 in prostate cancer cells, and activation of autophagy might be a potential strategy for improving its chemotherapeutic effects.

Cancer chemotherapy and pharmacology. 2015 Dec 08 [Epub ahead of print]

Yongqing Liu, Ming Wang, Dawei Wang, Xiaobin Li, Wei Wang, Hongxiang Lou, Huiqing Yuan

Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China. , Department of Biochemistry, Wannan Medical College, Wuhu, 241002, China. , Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China. , Department of Natural Product Chemistry, Shandong University School of Pharmaceutical Sciences, Jinan, 250012, China. , Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China. , Department of Natural Product Chemistry, Shandong University School of Pharmaceutical Sciences, Jinan, 250012, China. , Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China. 

PubMed

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