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Myeloma

PKA/AMPK signaling in relation to adiponectin’s antiproliferative effect on multiple myeloma cells

Leukemia volume 28, pages 2080–2089 (2014)Cite this article

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Abstract

Obesity increases the risk of developing multiple myeloma (MM). Adiponectin is a cytokine produced by adipocytes, but paradoxically decreased in obesity, that has been implicated in MM progression. Herein, we evaluated how prolonged exposure to adiponectin affected the survival of MM cells as well as putative signaling mechanisms. Adiponectin activates protein kinase A (PKA), which leads to decreased AKT activity and increased AMP-activated protein kinase (AMPK) activation. AMPK, in turn, induces cell cycle arrest and apoptosis. Adiponectin-induced apoptosis may be mediated, at least in part, by the PKA/AMPK-dependent decline in the expression of the enzyme acetyl-CoA-carboxylase (ACC), which is essential to lipogenesis. Supplementation with palmitic acid, the preliminary end product of fatty acid synthesis, rescues MM cells from adiponectin-induced apoptosis. Furthermore, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), an ACC inhibitor, exhibited potent antiproliferative effects on MM cells that could also be inhibited by fatty acid supplementation. Thus, adiponectin’s ability to reduce survival of MM cells appears to be mediated through its ability to suppress lipogenesis. Our findings suggest that PKA/AMPK pathway activators, or inhibitors of ACC, may be useful adjuvants to treat MM. Moreover, the antimyeloma effect of adiponectin supports the concept that hypoadiponectinemia, as occurs in obesity, promotes MM tumor progression.

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Acknowledgements

We thank RC Aguiar, MD, PhD, for critical review of the manuscript and LQ Dong, PhD, for useful discussions during this research. Grant number KL2TR001118 from the National Institutes of Health’s National Center for Advancing Translational Sciences and a Multiple Myeloma Research Foundation Research Fellow Award (EAM) supported this work.

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Authors and Affiliations

  1. Division of Hematopathology, Department of Pathology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    E A Medina, K Oberheu, S R Polusani, V Ortega & G V N Velagaleti

  2. Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    B O Oyajobi

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Medina, E., Oberheu, K., Polusani, S. et al. PKA/AMPK signaling in relation to adiponectin’s antiproliferative effect on multiple myeloma cells. Leukemia 28, 2080–2089 (2014). https://doi.org/10.1038/leu.2014.112

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