Adiponectin receptor activation inhibits prostate cancer xenograft growth

in Endocrine-Related Cancer
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  • 1 Australian Prostate Cancer Research Centre – Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia
  • | 2 Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
  • | 3 Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  • | 4 Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
  • | 5 School of Chemistry, University of Melbourne, Melbourne, Victoria, Australia
  • | 6 OLPE, LLC, Audubon, Pennsylvania, USA
  • | 7 Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary

Correspondence should be addressed to L K Philp: lisa.philp@qut.edu.au
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Adiponectin is an adipokine originally identified as dysregulated in obesity, with a key role in insulin sensitisation and in maintaining systemic energy balance. However, adiponectin is progressively emerging as having aberrant signalling in multiple disease states, including prostate cancer (PCa). Circulating adiponectin is lower in patients with PCa than in non-malignant disease, and inversely correlates with cancer severity. More severe hypoadiponectinemia is observed in advanced PCa than in organ-confined disease. Given the crossover between adiponectin signalling and several cancer hallmark pathways that influence PCa growth and progression, we hypothesised that targeting dysregulated adiponectin signalling may inhibit tumour growth and progression. We, therefore, aimed to test the efficacy of correcting the hypoadiponectinemia and dysregulated adiponectin signalling observed in PCa, a world-first PCa therapeutic approach, using peptide adiponectin receptor (ADIPOR) agonist ADP355 in mice bearing subcutaneous LNCaP xenografts. We demonstrate significant evidence for PCa growth inhibition by ADP355, which slowed tumour growth and delayed progression of serum PCa biomarker, prostate-specific antigen (PSA), compared to vehicle. ADP355 conferred a significant advantage by increasing time on treatment with a delayed ethical endpoint. mRNA sequencing and protein expression analyses of tumours revealed ADP355 PCa growth inhibition may be through altered cellular energetics, cellular stress and protein synthesis, which may culminate in apoptosis, as evidenced by the increased apoptotic marker in ADP355-treated tumours. Our findings highlight the efficacy of ADP355 in targeting classical adiponectin-associated signalling pathways in vivo and provide insights into the promising future for modulating adiponectin signalling through ADIPOR agonism as a novel anti-tumour treatment modality.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
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