Adelaide Medical School, University of Adelaide, Adelaide, Australia.
South Australian Health and Medical Research Institute, Adelaide, Australia.
Elife. 2021 Aug 12;10:e62592. doi: 10.7554/eLife.62592.
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 () as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 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-C 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.
雄激素受体 (AR) 信号轴和细胞代谢的改变是前列腺癌的标志。本研究通过揭示 AR 与戊糖磷酸途径 (PPP) 之间的新联系，提供了对这两个标志的深入了解。具体而言，我们发现 6-磷酸葡萄糖酸脱氢酶 (6PGD) 是一种雄激素调节基因，在前列腺癌中上调。AR 通过激活固醇调节元件结合蛋白 1 (SREBP1) 间接增加 6PGD 的表达。因此，6PGD、AR 或 SREBP1 的缺失导致 PPP 活性受到抑制，这可以通过 1,2-C 葡萄糖代谢通量分析来揭示。6PGD 的敲低也会损害前列腺癌细胞的生长并引发其死亡，至少部分原因是氧化应激增加。我们使用两种特异性抑制剂 physcion 和 S3 研究了靶向 6PGD 的治疗潜力，并在多种前列腺癌模型中观察到了显著的抗癌活性，包括侵袭性、抗治疗的去势抵抗疾病模型以及前瞻性收集的患者来源的肿瘤外植体。靶向 6PGD 与两种重要的肿瘤抑制机制相关：首先，AMP 激活的蛋白激酶 (AMPK) 的活性增加，抑制了乙酰辅酶 A 羧化酶 1 (ACC1) 和雷帕霉素复合物 1 (mTORC1) 调节的合成代谢促进途径；其次，AR 泛素化增强，与 AR 蛋白水平和活性降低有关。支持 AR 和 6PGD 之间正反馈的生物学相关性，两种因素的药理学联合靶向比单一药物治疗更有效地抑制前列腺癌细胞的生长。总的来说，这项工作为前列腺癌失调代谢提供了新的见解，并为进一步研究 AR 和 PPP 的联合靶向作为一种新的治疗策略提供了动力。
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