Androgen-Dependent Prostate Cancer Cells Reprogram Their Metabolic Signature upon GLUT1 Upregulation by Manganese Superoxide Dismutase

Abstract

Prostate cancer is the second leading cause of cancer in men across the globe. The prostate gland accounts for some unique glycolytic metabolic characteristics, which causes the metabolic features of prostate tumor initiation and progression to remain poorly characterized. The mitochondrial superoxide dismutase (SOD2) is one of the major redox metabolism regulators. This study points out SOD2 as one major regulator for both redox and glycolytic metabolism in prostate cancer. SOD2 overexpression increases glucose transporter GLUT-1 and glucose uptake. This is not an insulin-mediated effect and seems to be sex-dependent, being present in male mice only. This event concurs with a series of substantial metabolic rearrangements at cytoplasmic and mitochondrial level. A concomitant decrease in glycolytic and pentose phosphate activity, and an increase in electron transfer in the mitochondrial electronic chain, were observed. The Krebs Cycle is altered to produce amino-acid intermediates by decreasing succinate dehydrogenase. This in turn generates a 13-fold increase in the oncometabolite succinate. The protein energy sensor AMPK is decreased at basal and phosphorylated levels in response to glucose deprivation. Finally, preliminary results in prostate cancer patients indicate that glandular areas presenting high levels of SOD2 show a very strong correlation with GLUT-1 protein levels (R2 = 0.287 p-value < 0.0001), indicating that in patients there may exist an analogous phenomenon to those observed in cell culture and mice.

Insulin-dependent GLUT4 is a risk factor for cancer in the prostate

“…Although glucose uptake is higher in androgen-resistant cells, the levels of labelled lactate and, thus, glycolytic activity, are enhanced in androgen-insensitive cells which indicates the transition from glycolytic to oxidative in hormone resistant phenotypes previously described [36]. In addition to a decrease in aerobic glycolysis, as indicate m + 3 lactate molar fraction, some metabolites of the TCA, like succinate, incorporated lower levels of 13 C in PC-3 than LNCaP cells according to previous results [41]. A possible explanation for these results is that AR signalling reduces the utilisation of glucose through pyruvate production through the upregulation of PPP.…”

Insights into Manganese Superoxide Dismutase and Human Diseases

“…Similarly, upregulation of MnSOD in cancer cells engaged AMPK to perform and sustain the Warburg effect, therefore supporting cancer cell survival [224]. Cells with a high level of MnSOD were more resistant to glucose-deprivation-induced cell death because MnSOD increased glucose uptake, glucose transporter member 1 (GLUT-1) availability, and OXPHOS electron transfer [225]. These results indicate a vital role of MnSOD in cancer glycolytic metabolism reprogramming, which deserves more in-depth mechanistic studies.…”

Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies

“…Hence in this scenario, a therapeutic approach could also have a negative loop effect by causing an accumulation of a molecule that could work oppositely respect to the beneficial effect of the drug [ 46 ]. Moreover, also the anti-oxidant enzyme superoxide dismutase 2 (SOD2) has been shown to be indirectly involved also in the sustainment of succinate accumulation through a decreased activity of SDH and, intriguingly, an enhanced expression of Glut1 and glucose uptake in prostate cancer models [ 47 ], however these evidence need further validations in other biological systems. In this frame, CAFs and succinate accumulation has been reported play a key role in the context of prostate cancer.…”