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

Gillis, J. L.; Hinneh, J. A.; Ryan, N. K.; Irani, S.; Moldovan, M.; Shrestha, R. K.; Quek, L.-E.; Hoy, A. J.; Holst, J.; Centenera, M. M.; Mills, I. G.; Lynn, D. J.; Selth, L. A.; Butler, L. M.

doi:10.1101/2020.09.02.279356

bioRxiv · 10.1101/2020.09.02.279356

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

Gillis, J. L.·Hinneh, J. A.·Ryan, N. K.·Irani, S.·Moldovan, M.·Shrestha, R. K.·Quek, L.-E.·Hoy, A. J.·Holst, J.·Centenera, M. M.·Mills, I. G.·Lynn, D. J.·Selth, L. A.·Butler, L. M.

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Abstract

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.

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Gillis, J. L., Hinneh, J. A., Ryan, N. K., Irani, S., Moldovan, M., Shrestha, R. K., Quek, L.-E., Hoy, A. J., Holst, J., Centenera, M. M., Mills, I. G., Lynn, D. J., Selth, L. A., Butler, L. M.. 2020-09-03. A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth. https://doi.org/10.1101/2020.09.02.279356

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