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

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 ACC1 and mTOR; 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 PGD, 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.

Targeting MALAT1 Augments Sensitivity to PARP Inhibition by Impairing Homologous Recombination in Prostate Cancer.

“…Alternatively, small molecule inhibitor (enzalutamide) mediated pharmacological inhibition of AR signaling also results in a robust increase in MALAT1 expression in both LNCaP and VCaP cells, while no change was observed in 22RV1 cells ( Figure 5F) . In line with this, LNCaP cells (GSE152254) (54) treated with a lower concentration (1μM) of enzalutamide also show increased expression of MALAT1 as well as AR repressed genes, namely DDC and OPRK1 ( Supplemental Figure S4B). Conversely, a marked decrease in MALAT1 expression was noticed in VCaP cells stimulated with a sub-physiological concentration of synthetic androgen, R1881 (1 nM; GSE71797, (55) ( Supplemental Figure S4B).…”

Personalized Medicine for Prostate Cancer: Is Targeting Metabolism a Reality?

“…A more comprehensive investigation of lactate metabolism in prostate cancer is clearly warranted. Finally, the pentose phosphate pathway (PPP) is a glucose catabolic pathway that appears to be important in prostate tumor growth in AR/SREBP/6PGD-dependent manner (45). However, whether PPP plays a significant role in prostate cancer by generating nucleotide precursor or sustaining the NADPH pool for lipogenesis and redox homeostasis is yet to be elucidated.…”

The Integration of Metabolomics with Other Omics: Insights into Understanding Prostate Cancer

“…The interlink with glycolysis is seen after isomerization of ribulose-5-phosphate (R5P) using transketolase and transaldolase. PPP is controlled by G6PDH wherein studies have indicated that this enzyme is increased in PCa [387][388][389][390][391]. G6PDH, NAPDH, and ribose synthesis were all upregulated in PCa through the action of AR signaling [343,388].…”