Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

“…Metabolic flux of [ ]glutamine into TCA cycle intermediates was determined as previously described (47). Additional information for the experiments with [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glutamine can be found in the Supplemental Methods.…”

“…ADH-FE1 induced an increase in the NADPH to NADP ratio, but it did not induce depletion of citrate. Reductive carboxylation of glutamine-derived α-ketoglutarate is an important survival mechanism in mammalian cells and constitutes a pathway to maintain citrate synthesis and lipogenesis in oxygen-deprived cells (21,22,47,48). In contrast, cells expressing mutant IDH are no longer capable of performing reductive carboxylation and exhibit an increased dependence on oxidative mitochondrial metabolism (49,50).…”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Reductive carboxylation, the importance of which is still somewhat controversial 88 , seems to be a major source of carbon for lipid synthesis in cancer cells that are hypoxic, have constitutive hypoxia-inducible factor-α (HIFα) stabilization or have mitochondrial defects [89][90][91][92] . Although the contribution of reductive carboxylation to lipid formation from glutamine remains unclear due to the possibility of isotope exchange 88 , studies suggest that reductive carboxylation occurs in vivo and can support lipogenesis for tumor growth and progression 89,93,94 and can also control the levels of mitochondrial reactive oxygen species (ROS) 95 .…”

“…Similarly, the synergism between glutamine withdrawal and chemical activation of the ISR with the retinoid-derivative fenretinide 65 shows that glutamine can suppress this stress response through various mechanisms, as discussed above. While invasive and metastatic cells have not specifically been studied for their sensitivity to glutaminolysis inhibition, it has been shown that highly invasive ovarian cancer cells have increased glutamine dependence compared to less invasive cells 181 , and metastatic prostate tumors show increased glutamate availability and dependence on glutamine uptake 93,182 . Indeed, genetic inhibition of glutaminase was shown to prevent epithelial-to-mesenchymal transition, a key step in tumor cell invasiveness and eventual metastasis 183 .…”

Targeting SREBPs for treatment of the metabolic syndrome

“…Increased SREBP-1 activity and de novo lipid synthesis is a critical feature of a prostate cancer metabolic program that depends on activated steroid receptor coactivator 2 [86]. Moreover, inhibition of SREBPs attenuated the growth of glioblastoma cell xenografts [87] and SREBPs defined a gene signature associated with poor survival in glioblastoma [88].…”