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Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation. J Biol Chem 2018 09 21;293(38):14891-14904

Date

08/09/2018

Pubmed ID

30087121

Pubmed Central ID

PMC6153299

DOI

10.1074/jbc.RA117.001469

Scopus ID

2-s2.0-85054023214   43 Citations

Abstract

Mutations in the KRAS proto-oncogene are present in 50% of all colorectal cancers and are increasingly associated with chemotherapeutic resistance to frontline biologic drugs. Accumulating evidence indicates key roles for overactive KRAS mutations in the metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis in cancer cells. Here, we sought to exploit the more negative membrane potential of cancer cell mitochondria as an untapped avenue for interfering with energy metabolism in KRAS variant-containing and KRAS WT colorectal cancer cells. Mitochondrial function, intracellular ATP levels, cellular uptake, energy sensor signaling, and functional effects on cancer cell proliferation were assayed. 3-Carboxyl proxyl nitroxide (Mito-CP) and Mito-Metformin, two mitochondria-targeted compounds, depleted intracellular ATP levels and persistently inhibited ATP-linked oxygen consumption in both KRAS WT and KRAS variant-containing colon cancer cells and had only limited effects on nontransformed intestinal epithelial cells. These anti-proliferative effects reflected the activation of AMP-activated protein kinase (AMPK) and the phosphorylation-mediated suppression of the mTOR target ribosomal protein S6 kinase B1 (RPS6KB1 or p70S6K). Moreover, Mito-CP and Mito-Metformin released Unc-51-like autophagy-activating kinase 1 (ULK1) from mTOR-mediated inhibition, affected mitochondrial morphology, and decreased mitochondrial membrane potential, all indicators of mitophagy. Pharmacological inhibition of the AMPK signaling cascade mitigated the anti-proliferative effects of Mito-CP and Mito-Metformin. This is the first demonstration that drugs selectively targeting mitochondria induce mitophagy in cancer cells. Targeting bioenergetic metabolism with mitochondria-targeted drugs to stimulate mitophagy provides an attractive approach for therapeutic intervention in KRAS WT and overactive mutant-expressing colon cancer.

Author List

Boyle KA, Van Wickle J, Hill RB, Marchese A, Kalyanaraman B, Dwinell MB

Authors

Kathleen A. Boyle PhD Adjunct Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Ronald Blake Hill PhD Professor in the Biochemistry department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Chair, Professor in the Biophysics department at Medical College of Wisconsin
Adriano Marchese PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Adenylate Kinase
Autophagy-Related Protein-1 Homolog
Cell Line, Tumor
Cell Proliferation
Colonic Neoplasms
Energy Metabolism
Genes, ras
Humans
Intracellular Signaling Peptides and Proteins
Mechanistic Target of Rapamycin Complex 1
Membrane Potential, Mitochondrial
Mitochondria
Oxidative Phosphorylation
Signal Transduction