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Underactivation of the adiponectin–adiponectin receptor 1 axis in clear cell renal cell carcinoma: implications for progression

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Abstract

Energy-sensing pathways, normally coordinated by 5′ AMP-activated protein kinase (AMPK), are dysregulated in renal cell carcinoma (RCC). Obesity can accentuate the pre-existing pro-tumorigenic metabolic machinery in RCC cells through its associated obesogenic hormonal milieu, characterized by lower circulating levels of adiponectin. In RCC patients, low adiponectin levels associate clinically with more aggressive disease. We investigated the adiponectin signaling pathway in RCC, focusing on adiponectin receptor 1 (AdipoR1) and associated activation of AMPK. AdipoR1 protein in RCC and normal surrounding renal tissues was determined by Western blot analysis and immunohistochemistry. Anti-tumorigenic effects of adiponectin in RCC cells in vitro were investigated via VEGF and MMP ELISA and invasion assays. Using in vivo models of RCC, the effect of AdipoR1-knockdown (shRNA) on tumor latency, growth and dissemination were determined. AdipoR1 protein was significantly reduced in clear cell RCC specimens. Adiponectin treatment inhibited VEGF, MMP-2 and MMP-9 secretion and activity and invasive and migratory capacities of RCC cells. AMPKα1-knockdown (shRNA) attenuated adiponectin’s effects. In cells stably expressing AdipoR1-specific shRNA, AMPK activation by adiponectin was significantly reduced compared to cells expressing control shRNA. In vivo, AdipoR1 knockdown increased the growth, dissemination and angiogenesis of RCC. These findings suggest that deficiencies in the entire adiponectin hormonal axis (the hormone and its receptor) result in underactivation of AMPK leading to increased angiogenic and invasive capacities of RCC. The established link between obesity and RCC can therefore be further explained by the adiponectin deficiency in obese individuals together with reduced AdipoR1 protein in RCC.

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Acknowledgments

We are indebted to Drs. S. Popovic and J.C. Cutz, for sharing their expertise in pathology, to Dr. J.P. Lu for excellent technical assistance, and Dr. A. Kapoor for providing clinical RCC specimens. This work was supported by the Canadian Institutes of Health Research (Grant 93465), a young investigators research grant by the Northeastern section of the American Urological Association, McMaster Surgical Associates, and an early career award by Hamilton Health Sciences (to JHP).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Urology, Department of Surgery, McMaster University, Hamilton, ON, Canada

    Nir Kleinmann, Wilhelmina C. M. Duivenvoorden, Sarah N. Hopmans, Laura K. Beatty, ShengJun Qiao, Daniel Gallino, Athanasios Paschos & Jehonathan H. Pinthus

  2. Juravinski Cancer Center, McMaster University, Hamilton, ON, Canada

    Wilhelmina C. M. Duivenvoorden, Sarah N. Hopmans & Daniel Gallino

  3. Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON, Canada

    Laura K. Beatty, Sarka Lhotak & Richard C. Austin

  4. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

    Dean Daya

  5. Department of Surgical Oncology, Juravinski Hospital, 3rd Floor, Room B-148, 711 Concession Street, Hamilton, ON, L8V 1C3, Canada

    Jehonathan H. Pinthus

  6. Mcmaster Institute of Urology at St. Joseph’s Healthcare, Hamilton, ON, Canada

    Nir Kleinmann, Wilhelmina C. M. Duivenvoorden, Sarah N. Hopmans, Laura K. Beatty, Athanasios Paschos & Jehonathan H. Pinthus

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  1. Nir Kleinmann
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Kleinmann, N., Duivenvoorden, W.C.M., Hopmans, S.N. et al. Underactivation of the adiponectin–adiponectin receptor 1 axis in clear cell renal cell carcinoma: implications for progression. Clin Exp Metastasis 31, 169–183 (2014). https://doi.org/10.1007/s10585-013-9618-1

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