Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells.
Up-regulation of lipogenesis by androgen is one of the most characteristic metabolic features of LNCaP prostate cancer cells. The present study revealed that androgen increases glucose utilization for de novo lipogenesis in LNCaP cells through the activation of HK2 (hexokinase 2) and activation of the cardiac isoform of PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). Activation of PKA (cAMP-dependent protein kinase) by androgen increased phosphorylation of CREB [CRE (cAMP-response element)-binding protein], which in turn bound to CRE on the promoter of the HK2 gene resulting in transcriptional activation of the HK2 gene. Up-regulation of PFKFB2 expression was mediated by the direct binding of ligand-activated androgen receptor to the PFKFB2 promoter. The activated PI3K (phosphoinositide 3-kinase)/Akt signalling pathway in LNCaP cells contributes to the phosphorylation of PFKFB2 at Ser466 and Ser483, resulting in the constitutive activation of PFK-2 (6-phosphofructo-2-kinase) activity. Glucose uptake and lipogenesis were severely blocked by knocking-down of PFKFB2 using siRNA (small interfering RNA) or by inhibition of PFK-2 activity with LY294002 treatment. Taken together, our results suggest that the induction of de novo lipid synthesis by androgen requires the transcriptional up-regulation of HK2 and PFKFB2, and phosphorylation of PFKFB2 generated by the PI3K/Akt signalling pathway to supply the source for lipogenesis from glucose in prostate cancer cells.
Moon
Jong-Seok
JS
Department of Biochemistry and Molecular Biology, Institute of Genetic Science, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Science, Yonsei University, College of Medicine, Seodaemungu, Seoul, Korea.
Jin
Won-Ji
WJ
Kwak
Jin-Hye
JH
Kim
Hyo-Jeong
HJ
Yun
Mi-Jin
MJ
Kim
Jae-Woo
JW
Park
Sahng Wook
SW
Kim
Kyung-Sup
KS
D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation
D000728:Androgens; D008055:Lipids; D011944:Receptors, Androgen; D019869:Phosphatidylinositol 3-Kinases; D006593:Hexokinase; C555744:PFKFB2 protein, human; D025481:Phosphofructokinase-2