Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway

Yuan, Lingqin; Sheng, Xiugui; Willson, Adam K.; Roque, Dario R.; Stine, Jessica E.; Guo, Hui; Jones, Hannah M.; Zhou, Chunxiao; Bae‐Jump, Victoria L.

doi:10.1530/erc-15-0192

Cited by 97 publications

(78 citation statements)

References 56 publications

(53 reference statements)

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“…This resulted in a more aggressive behavior as evidenced in higher proliferation rate and increased tumor growth (42). A correlation between glutamine dependency and increased aggressiveness was also seen in ovarian cancer, where it was shown that glutamine is required to promote cell proliferation (43). In addition, it was demonstrated that certain ovarian cancer cell lines are glutamine-dependent while others are glucose dependent, and importantly, glutamine dependency correlated with migration and invasiveness (44).…”

Section: Discussionmentioning

confidence: 93%

Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells

Zinger

Merenbakh-Lamin

Klein

et al. 2019

Clinical Cancer Research

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Purpose: Mutations in the ligand-binding domain (LBD) of estrogen receptor a (ER) confer constitutive transcriptional activity and resistance to endocrine therapies in patients with breast cancer. Accumulating clinical data suggest adverse outcome for patients harboring tumors expressing these mutations. We aimed to elucidate mechanisms conferring this aggressive phenotype.Experimental Design: Cells constitutively expressing physiologic levels of ER-harboring activating LBD mutations were generated and characterized for viability, invasiveness, and tumor formation in vivo. Gene expression profile was studied using microarray and RNAseq technologies. Metabolic properties of the cells were assessed using global metabolite screen and direct measurement of metabolic activity.Results: Cells expressing mutated ER showed increased proliferation, migration, and in vivo tumorigenicity compared with cells expressing the wild-type ER (WT-ER), even in the presence of estrogen. Expression of the mutated ER was associated with upregulation of genes involved in invasion and metastases, as well as elevation of genes associated with tumor cell metabolism. Indeed, a metabolic examination revealed four distinct metabolic profiles: WT-ER-expressing cells either untreated or estrogen treated and mutated ER-expressing cells either untreated or estrogen treated. Pathway analyses indicated elevated tricarboxylic acid cycle activity of 537S-ERexpressing cells. Thus, while WT-ER cells were mostly glucosedependent, 537S-ER were not addicted to glucose and were able to utilize glutamine as an alternative carbon source.Conclusions: Taken together, these data indicate estrogenindependent rewiring of breast cancer cell metabolism by LBD-activating mutations. These unique metabolic activities may serve as a potential vulnerability and aid in the development of novel treatment strategies to overcome endocrine resistance.

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Section: Discussionmentioning

confidence: 93%

Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells

Zinger

Merenbakh-Lamin

Klein

et al. 2019

Clinical Cancer Research

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“…In a previous report, glutamine promoted ovarian cancer cell proliferation through the mTOR/S6 pathway, suggesting a close association between amino acid metabolism and the mTOR signaling pathway (40). ASCT2 mediates the uptake of glutamine in tumors.…”

Section: Univariate Analysismentioning

confidence: 83%

Clinical associations between ASCT2 and p‑mTOR in the pathogenesis and prognosis of epithelial ovarian cancer

Guo

Wang

et al. 2018

Oncol Rep

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Alanine serine cysteine-preferring transporter 2 (ASCT2; also known as SLC1A5) is an important glutamine transporter, and it serves a crucial role in tumor growth and progression. ASCT2 is highly expressed in numerous types of cancer, but the pathological significance of its expression in epithelial ovarian cancer (EOC) remains unclear. The mechanistic target of rapamycin (mTOR) level is hyperelevated in a number of tumor types, including ovarian cancer. The aim of the present study was to elucidate the prognostic role of ASCT2 and phosphorylated (p)-mTOR in EOC. The levels of ASCT2 and p-mTOR/mTOR were detected in normal ovarian tissues, benign ovarian tumors, borderline ovarian tumors and EOC tissues by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot assays. The protein levels of ASCT2 and p-mTOR in EOC patients were then detected by immunohistochemistry (IHC). Furthermore, EOC tumor sections were stained for Ki-67 and cluster of differentiation 34 (CD34) to assess proliferation and microvessel density by IHC. The results of RT-qPCR and western blot analysis demonstrated that ASCT2 and p-mTOR protein levels were significantly higher in EOC tissues compared with those in other groups. IHC analysis of 104 EOC tissues suggested that ASCT2 expression was associated with clinicopathological parameters, including International Federation of Gynecology and Obstetrics stage, pathological grade, serum cancer antigen 125 level, Ki-67 status and CD34 status. Kaplan-Meier survival curve analysis indicated that high expression of ASCT2 and p-mTOR were important factors predicting a poor prognosis for patients with EOC. The expression levels of ASCT2 and p-mTOR in EOC were positively correlated (r=0.385, P<0.001). This positive correlation between ASCT2 and p-mTOR indicates that they have a synergistic effect on the growth and development of early EOC. The combined detection of ASCT2 and p-mTOR may serve as a potential marker to inform diagnosis, postoperative follow-up requirements and targeted therapy options for patients with early-stage EOC, but not for terminal-stage patients.

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“…The primary source of nutrition that provides bioenergy in cancer cells to proliferate is glutamine. [24] The increasing of glutaminolysis is one of the characteristics of metabolic changes in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…[25] In cancer cells, the conversion of glutamine to lactate has increased compared to healthy cells. [24] Because of its essential function in cancer cell metabolism, if glutamine deficiency occurs, cell growth inhibition can even induce apoptosis. [24] Yang et al found that the level of cancer cell dependence on glutamine was highly correlating with the rate of cancer invasion.…”

Section: Discussionmentioning

confidence: 99%

“…[24] Because of its essential function in cancer cell metabolism, if glutamine deficiency occurs, cell growth inhibition can even induce apoptosis. [24] Yang et al found that the level of cancer cell dependence on glutamine was highly correlating with the rate of cancer invasion. Cancer with a high rate of invasion is very dependent on the availability of glutamine.…”

Section: Discussionmentioning

confidence: 99%

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The Combination of Serum Biomarker (CA-125, FASN, and GLS) as a Predictor Suboptimal Cytoreduction in Epithelial Ovarian Cancer

Winarno

Hidayat

Soetopo

et al. 2020

Preprint

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Purpose. Cytoreduction has an important role in improving the survival rate of epithelial ovarian cancer (EOC) patients. The use of preoperative CA-125 as an optimal predictor cytoreduction in patients with ovarian cancer is still controversial. This study aimed to assess the ability of preoperative serum CA125, FASN and GLS as a predictor of cytoreductive surgery in epithelial ovarian cancer (EOC). This observational-analytic cross-sectional study included 109 women diagnosed with epithelial ovarian cancer (EOC) between 2017-2019, who had serum CA-125, GLS, FASN measured preoperatively and underwent cytoreductive surgery. Result. The average value of serum CA-125, FASN, and GLS in the suboptimal cytoreduction were higher than the optimal cytoreduction group. The cut off point (COP) of CA-125 was 248.55 (p=0.0001) with 73.2% sensitivity and 73.6% specificity, FASN was 0.445 (p=0.017) with 62.5% sensitivity and 60.4% specificity, and GLS was 22.895 (p=0.0001) with 73.2% sensitivity and 75.5% specificity. The COP value of CA-125 and GLS combined was 29.16 (p=0.0001) with sensitivity 82.1% and spesificity 73.6%, while the COP of CA-125, GLS, and FASN combined was 0.83 (p=0.0001) with 87.5% sensitivity and 73.6% specificity. If the value of biomarker serum more than COP will more likely have suboptimal cytoreductive surgery. Conclusion. The role of CA125, FASN and GLS levels in predicting suboptimal cytoreductive surgery for patients with ovarian cancer seems questionable. However, the combination of CA-125 and GLS or CA-125, FASN and GLS are able to increase the sensitivity, specificity, and accuracy classification to predict suboptimal cytoreductive surgery.

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Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway

Cited by 97 publications

References 56 publications

Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells

Ligand-binding Domain–activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells

Clinical associations between ASCT2 and p‑mTOR in the pathogenesis and prognosis of epithelial ovarian cancer

The Combination of Serum Biomarker (CA-125, FASN, and GLS) as a Predictor Suboptimal Cytoreduction in Epithelial Ovarian Cancer

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