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Adiponectin receptor activation inhibits prostate cancer xenograft growth

Abstract

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.

Type Journal
ISBN 1479-6821 (Electronic) 1351-0088 (Linking)
Authors Philp, L. K.; Rockstroh, A.; Lehman, M.; Sadowski, M. C.; Bartonicek, N.; Wade, J. D.; Otvos, L.; Nelson, C. C.
Responsible Garvan Author Dr Nenad Bartonicek
Publisher Name ENDOCRINE-RELATED CANCER
Published Date 2020-12-01
Published Volume 27
Published Issue 12
Published Pages 711-729
Status Published in-print
DOI 10.1530/ERC-20-0297
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/33112829