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

被引:129
作者
Tsouko, E. [1 ]
Khan, A. S. [1 ]
White, M. A. [1 ]
Han, J. J. [1 ]
Shi, Y. [1 ]
Merchant, F. A. [2 ]
Sharpe, M. A. [3 ]
Xin, L. [4 ,5 ,6 ]
Frigo, D. E. [1 ,7 ]
机构
[1] Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX 77204 USA
[2] Univ Houston, Dept Engn Technol, Houston, TX 77204 USA
[3] Houston Methodist Res Inst, Dept Neurosurg, Houston, TX USA
[4] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[5] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA
[6] Dan L Duncan Canc Ctr, Houston, TX USA
[7] Houston Methodist Res Inst, Ctr Genom Med, Houston, TX USA
基金
美国国家科学基金会;
关键词
prostate cancer; G6PD; pentose phosphate pathway; androgen receptor; mTOR; PTEN; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE G6PD; OXIDATIVE STRESS; KINASE; METABOLISM; PTEN; PROLIFERATION; PROGRESSION; ACTIVATION; INHIBITION; EXPRESSION;
D O I
10.1038/oncsis.2014.18
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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; Pten(f/f) and K8-CreER(T2); Pten(f/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.
引用
收藏
页码:e103 / e103
页数:10
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