Quek, L.-E. | Search bioRxiv

bioRxiv2020

A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth

Alterations to androgen receptor (AR) signalling and cellular metabolism are hallmarks of prostate cancer. This study uncovers a novel link between AR and the pentose phosphate pathway (PPP) through 6-phosphogluoconate dehydrogenase (6PGD), an androgen-regulated gene that is upregulated in prostate cancer. Knockdown of 6PGD impairs growth and elicits death of prostate cancer cells, at least in part due to oxidative stress. Targeting 6PGD using 2 specific inhibitors, physcion and S3, was efficacious in multiple models of prostate cancer, including aggressive castration-resistant models. Importantly, S3 also suppressed proliferation of clinical patient-derived explants (PDEs). Mechanistically, 6PGD decreased expression and activity of AR in cell lines and PDEs, revealing a novel positive feedback loop between these factors. The enhanced efficacy of co-targeting AR and 6PGD further supported the biological relevance of this feedback. This work provides insight into the dysregulated metabolism of prostate cancer and supports investigation of co-targeting AR and the PPP.

cancer biology↗

bioRxiv2020

EXERCISE-INDUCED BENEFITS ON GLUCOSE HANDLING IN A MODEL OF DIET-INDUCED OBESITY ARE REDUCED BY CONCURRENT NICOTINAMIDE MONONUCLEOTIDE

ABSTRACTObjective Almost 40% of adults worldwide are classified as overweight or obese. Exercise is a beneficial intervention in obesity, partly due to increases in mitochondrial activity, with a potential role for the concomitant increase in nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that increasing NAD+ levels through pharmacological supplementation with precursors such as nicotinamide mononucleotide (NMN) improved metabolic health in high fat diet (HFD) fed mice. We examined the combined effects of NMN and treadmill exercise on the metabolic dysregulation in HFD-induced obesity.Methods Five-week old female C57BL/6J mice were exposed to control diet or HFD. Mice fed HFD were treated with NMN in drinking water (400mg/kg; HNMN), treadmill exercise (HEx) or combined NMN and exercise (HNEx).Results Unexpectedly, NMN administration impaired several aspects of exercise-induced benefits in HFD mice, including glucose tolerance, glucose stimulated insulin secretion from islets and reduced hepatic triglyceride accumulation. Mechanistically, HNEx mice displayed increased antioxidant and reduced prooxidant gene expression in both islets and muscle, suggesting that altered redox status is associated with the loss of exercise-induced health benefits with NMN co-treatment.Conclusion Our data show that NMN treatment blocks the beneficial metabolic effects of exercise in a mouse model of diet-induced obesity in association with disturbances in redox metabolism.HighlightsNMN dampened exercise-induced benefits on glucose handling in diet-induced obesity.NMN administration in exercise enhanced ratio of antioxidants to prooxidants.We suggest NMN administration may not be beneficial when NAD+ levels are replete.Competing Interest StatementL.E.W. is an inventor on patents licensed to Metro Biotech NSW and to Jumpstart Fertility, and has received sponsored research funding from both companies. He is an advisor and shareholder in EdenRoc Sciences (Metro Biotech NSW, Metro Biotech, Liberty Biosecurity), Life Biosciences LLC and its daughter companies (Jumpstart Fertility, Continuum Biosciences, Senolytic Therapeutics, Selphagy, Animal Biosciences, Iduna) and in Intravital Pty Ltd. L.E.W. provides consulting work for Life Biosciences.View Full Text

physiology↗