Abstract
Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.
Highlights
Altered cellular metabolism is a hallmark of cancer
To qualitatively and quantitatively compare downstream responses to androgen receptor (AR) ablation and AR antagonism, LNCaP cells were treated with AR siRNA or enzalutamide (Enz; AR antagonism) and subsequently evaluated by RNA-s eq The experimental conditions were optimised to achieve comparable suppression of the canonical AR target, prostate specific antigen (PSA), which is encoded by the KLK3 gene (Figure 1A)
These results provide further evidence for the hypothesis that AR ablation is more effective at suppressing the AR-regulated transcriptome compared with AR antagonism, at least in this experimental system
Summary
Altered cellular metabolism is a hallmark of cancer. Perhaps the best characterised metabolic transformation in malignant cells is the so-c alled Warburg effect, in which cancer cells favour metabolism via glycolysis rather than the more efficient oxidative phosphorylation (Vander Heiden et al, 2009). The overall survival benefits of these newer ARPIs in men with CRPC are in the order of months (Recine and Sternberg, 2015), despite many tumours retaining dependence on AR (Robinson et al, 2015). These clinical observations highlight the ongoing dependence of CRPC on AR signalling and the intractable problems associated with therapies that inhibit this pathway. We demonstrate that 6PGD plays a key role in PCa growth and survival, at least in part through moderating oxidative stress, and uncover a novel feedback mechanism linking 6PGD and the AR signalling axis that provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy
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