Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer

Abstract

Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

“…In contrast with Warburg effect, recent data suggest that cancer cells have healthy mitochondria; however, they have upregulated glycolysis (36). Interestingly, our data suggest that O-ASCs promoted glycolysis in cancer cells by elevating NO synthesis, which has been shown to have inhibitory effects on enzymes involved in mitochondrial respiration.…”

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Resistance mechanisms can be overcome through the usage of combinatorial agents concomitantly tackling various routes of cell survival (e.g., cell metabolism) to synergistically kill cancerous cells. For example, a new metabolic analysis indicates that ovarian cancer may be susceptible to multidrug cocktails, particularly if the amounts of the drugs can be tailored to match the metabolic profile of a patient's tumor [47]. By measuring the ratio of glutamine amounts externally taken in to internally produced, prognosis could be determined, in that a high ratio directly correlated to tumor aggression and metastasis.…”

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

“…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 .…”