title: Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A.
abstract: Apoptolidin A was first isolated as a secondary metabolite of a Nocardiopsis sp. and is the founding member of a family of potential selective cancer cell toxins. We now report the isolation, production and pharmacological characterization of apoptolidins A and C from an alternate actinomycete producer, an Amycolatopsis sp. from soil samples collected in Indonesia. We investigated the action of apoptolidins A and C in representative human glioblastoma cells, lung cancer cells and mouse embryonic fibroblasts (MEFs) to better understand the mechanism of action of the known apoptolidins. Shifts in cellular metabolism in intact cells and the status of the AMP-activated protein kinase (AMPK) stress pathway in response to apoptolidin A were entirely consistent with the actions of an ATP synthase inhibitor. We find the metabolic phenotype of the cell to be a critical determinant of apoptolidin sensitivity and the likely basis for cancer cell selectivity. The apoptolidins induce indirect activation of AMPK and trigger autophagy in sensitive cell types without significant inhibition of mTORC1. Human U87-MG glioblastoma cells and wild type MEFs showed increased phosphorylation of AMPK (Thr172), ACC (Ser79) and ULK1 (Ser555), whereas AMPKα-null MEFs and more glycolytic SF-295 glioblastoma cells lacked this response. Although both are reported to be selective inhibitors of mitochondrial ATP synthase, differences between apoptolidin- and oligomycin A-induced responses in cells indicate that the action of these macrolides is not identical.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Serrill
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Tan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Fotso
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Justyna
authors.initials: J
authors.lastname: Sikorska
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Noer
authors.initials: N
authors.lastname: Kasanah
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hau
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: McPhail
authors.affiliation: Department of Soil Science and Land Resources, Bogor Agricultural University, Bogor, Indonesia; Indonesian Center for Biodiversity and Biotechnology, Bogor, Indonesia.
authors.forename: Dwi Andreas
authors.initials: DA
authors.lastname: Santosa
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: T Mark
authors.initials: TM
authors.lastname: Zabriskie
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Taifo
authors.initials: T
authors.lastname: Mahmud
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Proteau
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA. Electronic address: jane.ishmael@oregonstate.edu.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Ishmael
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018942:Macrolides / Q000302:isolation & purification / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009840:Oligomycins / Q000302:isolation & purification / Q000494:pharmacology*; D011753:Pyrones / Q000302:isolation & purification / Q000494:pharmacology*; D012988:Soil Microbiology
chemical_list: D018942:Macrolides; D009840:Oligomycins; D011753:Pyrones; C506738:apoptolidin A; C509786:apoptolidin C; C031004:oligomycin A; D055372:AMP-Activated Protein Kinases
keywords: 2-Deoxyglucose (PubChem CID: 108223); Apoptolidin A; Apoptolidin A (PubChem CID: 46882478); Bafilomycin A1 (PubChem CID 6436223); Coibamide A; Compound C (PubChem CID 11524144); Mitochondrial inhibitor; Oligomycin A; Oligomycin A (PubChem CID: 6450197); Warburg effect