Regulation of the pentose phosphate pathway by an androgen receptor–mTOR-mediated mechanism and its role in prostate cancer cell growth

Abstract

Cancer cells display an increased demand for glucose. Therefore, identifying the specific aspects of glucose metabolism that are involved in the pathogenesis of cancer may uncover novel therapeutic nodes. Recently, there has been a renewed interest in the role of the pentose phosphate pathway in cancer. This metabolic pathway is advantageous for rapidly growing cells because it provides nucleotide precursors and helps regenerate the reducing agent NADPH, which can contribute to reactive oxygen species (ROS) scavenging. Correspondingly, clinical data suggest glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, is upregulated in prostate cancer. We hypothesized that androgen receptor (AR) signaling, which plays an essential role in the disease, mediated prostate cancer cell growth in part by increasing flux through the pentose phosphate pathway. Here, we determined that G6PD, NADPH and ribose synthesis were all increased by AR signaling. Further, this process was necessary to modulate ROS levels. Pharmacological or molecular inhibition of G6PD abolished these effects and blocked androgen-mediated cell growth. Mechanistically, regulation of G6PD via AR in both hormone-sensitive and castration-resistant models of prostate cancer was abolished following rapamycin treatment, indicating that AR increased flux through the pentose phosphate pathway by the mammalian target of rapamycin (mTOR)-mediated upregulation of G6PD. Accordingly, in two separate mouse models of Pten deletion/elevated mTOR signaling, Pb-Cre;Ptenf/f and K8-CreERT2;Ptenf/f, G6PD levels correlated with prostate cancer progression in vivo. Importantly, G6PD levels remained high during progression to castration-resistant prostate cancer. Taken together, our data suggest that AR signaling can promote prostate cancer through the upregulation of G6PD and therefore, the flux of sugars through the pentose phosphate pathway. Hence, these findings support a vital role for other metabolic pathways (that is, not glycolysis) in prostate cancer cell growth and maintenance.

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Interestingly, it was shown in vitro and in xenograft models that prostate cancer cell lines are highly dependent on the phosphofructokinase-fructose-bisphosphatase 2 isoform PFKFB4 and on glucose-6-phosphate dehydrogenase [152,168]. Specifically, PFKFB4 drives the balance of glucose-6-phosphate and fructose-1,6-bisphosphate towards glucose-6-phosphate.…”

“…Latter is used as a substrate in the glucose-6-phosphate dehydrogenase reaction, the initial step of the oxidative pentose phosphate pathway. This suggests that a substantial portion of the glucose taken up is channeled through the pentose phosphate pathway for reduction of NADP + and consequently glutathione disulfide, as well as for de novo nucleotide biosynthesis [168,169]. Besides, prostate cancer still relies on oxidative phosphorylation, which is enforced by the interaction with cancer-associated fibroblasts as shown for PC-3 cells [127].…”

“…Increased glycolytic metabolism is further supported by higher hexokinase 2 expression, which is at least partly triggered by androgen-receptor-dependent activation of PKA/CREB [162]. Interestingly, AMPK activation seems not to antagonize mTOR signaling status [161] and thus allows a mTOR-dependent induction of glucose-6-phosphate dehydrogenase and the oxidative pentose phosphate pathway [168], which allow an increased NADP + -reduction and nucleotide biosynthesis.…”

Cross-Sectional Study of Gene Expression Analysis Identifies Critical Biological Pathways and Key Genes Implicated in Non-Small Cell Lung Cancer

“…Up-regulated pathways related to metabolism would provide the necessity to cancer cells. At present, many study results have shown that these pathways were related to cancers, such as prostate cancer and breast cancer and so on (16,17). The current results showed that many metabolism pathways were significantly up-regulated in NSCLC, which mainly included purine metabolism (P value = 1.95e-44, ranked fourth), pyrimidine metabolism (P value = 1.01e-29, ranked fifth), glutathione metabolism (P value = 1.22e-27, ranked sixth), and amino sugar and nucleotide sugar metabolism (P value = 1.01e-21, ranked seventh).…”

Updates on Glucose 6-Phosphate Dehydrogenase (G6PD): From Prokaryotes to Human

“…Furthermore, the over expression G6PD was found to be required for prostate cancer cell proliferation [152] as its expression was increased upon androgen treatment in hormone sensitive prostate cancer cell lines. Thus it was suggested that G6PD activity could be used as a clinical marker for prostate cancer exams as its activity were found to be four times higher in carcinomas than in benign prostatic hyperplasia [152].…”