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The KISS1 metastasis suppressor appears to reverse the Warburg effect by shifting from glycolysis to mitochondrial beta-oxidation

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Abstract

The shift by cancer cells toward aerobic glycolysis (Warburg effect) confers selective advantages by utilizing nutrients (e.g., lipids, amino acids, and nucleotides) to build biomass. Lipogenesis is generally enhanced, and its inhibition diminishes proliferation and survival. Re-expression of the metastasis suppressor KISS1 in human melanoma cells results in greater mitochondrial biogenesis, inhibition of glycolysis, utilization of beta-oxidation to provide energy, elevated oxidation of exogenous fatty acids, and increased expression of early-phase lipogenesis genes at both mRNA and protein levels. Correspondingly, the energy sensor AMPKβ is phosphorylated, resulting in inhibitory phosphorylation of acetyl-CoA carboxylase (ACC), which is linked to enhanced beta-oxidation. Furthermore, PGC1α is required for KISS1-mediated phosphorylation of ACC and metastasis suppression. Collectively, these data further support the linkages between macromolecular metabolism and metastasis.

Key messages

• KISS1 alters fatty acid metabolism.

• There may be connections between metastasis and metabolism.

• PGC1alpha appears to be downstream mediator of KISS1 metastasis suppression.

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Acknowledgements

This study was supported by grants to DRW from Susan G. Komen for the Cure [SAC11037], the National Foundation for Cancer Research-Center for Metastasis Research, US National Cancer Institute RO1-CA134981, and using partial support from RO1-CA87728 and P30-CA168524. D.R. Welch is the Hall Family Professor of Molecular Medicine and a Kansas Bioscience Authority Eminent Scholar. This study also was supported by fellowship to SJM from the Kansas INBRE, P20 GM103418.

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  1. Wen Liu

    Present address: Department of Cancer Biology, Duke University Cancer Center, Durham, NC, USA

Authors and Affiliations

  1. Department of Cancer Biology, The University of Kansas Medical Center, 3901 Rainbow Blvd, Mail Stop 1071, Kansas City, KS, 66160, USA

    Sharon J. Manley, Wen Liu & Danny R. Welch

  2. The University of Kansas Cancer Center, Lawrence, KS, USA

    Danny R. Welch

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  1. Sharon J. Manley
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Correspondence to Danny R. Welch.

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Manley, S.J., Liu, W. & Welch, D.R. The KISS1 metastasis suppressor appears to reverse the Warburg effect by shifting from glycolysis to mitochondrial beta-oxidation. J Mol Med 95, 951–963 (2017). https://doi.org/10.1007/s00109-017-1552-2

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