Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A

Jeffrey D. Serrill, Michelle Tan, Serge Fotso, Justyna Sikorska, Noer Kasanah, Andrew M. Hau, Kerry L. McPhail, Dwi Andreas Santosa, Mark Zabriskie, Taifo Mahmud, Benoit Viollet, Philip J. Proteau, Jane E. Ishmael

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)251-265
Number of pages15
JournalBiochemical Pharmacology
Volume93
Issue number3
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

Fingerprint

AMP-Activated Protein Kinases
Fibroblasts
Cells
Mitochondrial Proton-Translocating ATPases
Glioblastoma
Phosphorylation
Macrolides
Metabolites
Metabolism
Adenosine Triphosphate
Chemical activation
Soils
oligomycin A
Indonesia
Actinobacteria
Autophagy
apoptolidin A
Lung Neoplasms
Neoplasms
Soil

Keywords

  • Apoptolidin A
  • Coibamide A
  • Mitochondrial inhibitor
  • Oligomycin A
  • Warburg effect

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry
  • Medicine(all)

Cite this

Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A. / Serrill, Jeffrey D.; Tan, Michelle; Fotso, Serge; Sikorska, Justyna; Kasanah, Noer; Hau, Andrew M.; McPhail, Kerry L.; Santosa, Dwi Andreas; Zabriskie, Mark; Mahmud, Taifo; Viollet, Benoit; Proteau, Philip J.; Ishmael, Jane E.

In: Biochemical Pharmacology, Vol. 93, No. 3, 01.02.2015, p. 251-265.

Research output: Contribution to journalArticle

Serrill, JD, Tan, M, Fotso, S, Sikorska, J, Kasanah, N, Hau, AM, McPhail, KL, Santosa, DA, Zabriskie, M, Mahmud, T, Viollet, B, Proteau, PJ & Ishmael, JE 2015, 'Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A', Biochemical Pharmacology, vol. 93, no. 3, pp. 251-265. https://doi.org/10.1016/j.bcp.2014.11.015
Serrill, Jeffrey D. ; Tan, Michelle ; Fotso, Serge ; Sikorska, Justyna ; Kasanah, Noer ; Hau, Andrew M. ; McPhail, Kerry L. ; Santosa, Dwi Andreas ; Zabriskie, Mark ; Mahmud, Taifo ; Viollet, Benoit ; Proteau, Philip J. ; Ishmael, Jane E. / Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A. In: Biochemical Pharmacology. 2015 ; Vol. 93, No. 3. pp. 251-265.
@article{deaacaaa20734d289c90558627a43503,
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.",
keywords = "Apoptolidin A, Coibamide A, Mitochondrial inhibitor, Oligomycin A, Warburg effect",
author = "Serrill, {Jeffrey D.} and Michelle Tan and Serge Fotso and Justyna Sikorska and Noer Kasanah and Hau, {Andrew M.} and McPhail, {Kerry L.} and Santosa, {Dwi Andreas} and Mark Zabriskie and Taifo Mahmud and Benoit Viollet and Proteau, {Philip J.} and Ishmael, {Jane E.}",
year = "2015",
month = "2",
day = "1",
doi = "10.1016/j.bcp.2014.11.015",
language = "English (US)",
volume = "93",
pages = "251--265",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A

AU - Serrill, Jeffrey D.

AU - Tan, Michelle

AU - Fotso, Serge

AU - Sikorska, Justyna

AU - Kasanah, Noer

AU - Hau, Andrew M.

AU - McPhail, Kerry L.

AU - Santosa, Dwi Andreas

AU - Zabriskie, Mark

AU - Mahmud, Taifo

AU - Viollet, Benoit

AU - Proteau, Philip J.

AU - Ishmael, Jane E.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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.

AB - 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.

KW - Apoptolidin A

KW - Coibamide A

KW - Mitochondrial inhibitor

KW - Oligomycin A

KW - Warburg effect

UR - http://www.scopus.com/inward/record.url?scp=84921712618&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921712618&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2014.11.015

DO - 10.1016/j.bcp.2014.11.015

M3 - Article

C2 - 25511868

AN - SCOPUS:84921712618

VL - 93

SP - 251

EP - 265

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 3

ER -