TY - JOUR
T1 - Regulation of the pentose phosphate pathway by an androgen receptor-mTOR-mediated mechanism and its role in prostate cancer cell growth
AU - Tsouko, E.
AU - Khan, A. S.
AU - White, M. A.
AU - Han, J. J.
AU - Shi, Y.
AU - Merchant, F. A.
AU - Sharpe, M. A.
AU - Xin, L.
AU - Frigo, D. E.
N1 - Funding Information:
We thank old and current members of the Frigo Laboratory for their technical support, critical reading of the manuscript and their suggestions. We also thank Carl Caruthers who assisted with initiating the NADPH assay in the laboratory and Fabiola F. Mehta who assisted with great technical support on the immunohistochemical protocol. This work was supported by NIH grants K01DK084205 (DEF), R03CA164908 (DEF), R00CA125937 (LX), DoD/PCRP grant W81XWH-12-1-0204 (DEF), CPRIT grant RP110005 (LX) and grants from the Texas Emerging Technology Fund and the Golfers Against Cancer (DEF).
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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 castrationresistant 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.
AB - 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 castrationresistant 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.
KW - G6PD
KW - PTEN
KW - androgen receptor
KW - mTOR
KW - pentose phosphate pathway
KW - prostate cancer
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U2 - 10.1038/oncsis.2014.18
DO - 10.1038/oncsis.2014.18
M3 - Article
C2 - 24861463
AN - SCOPUS:84906894979
SN - 2157-9024
VL - 3
JO - Oncogenesis
JF - Oncogenesis
IS - 5
M1 - e103
ER -