The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma

Momcilovic, Milica; Bailey, Sean T.; Lee, Jason T.; Fishbein, Michael C.; Braas, Daniel; Go, James; Graeber, Thomas G.; Parlati, Francesco; Demo, Susan D.; Li, Rui; Walser, Tonya C.; Gricowski, Michael; Shuman, R. H.; Ibarra, Julio A.; Fridman, Deborah; Phelps, Michael E.; Badran, Karam W.; John, Maie St.; Bernthal, Nicholas M.; Federman, Noah; Yanagawa, Jane; Dubinett, Steven M.; Sadeghi, Saman; Christofk, Heather R.; Shackelford, David B.

doi:10.1016/j.ccell.2018.04.002

Cited by 149 publications

(151 citation statements)

References 42 publications

Supporting

Mentioning

139

Contrasting

Order By: Relevance

“…This is in contrast to the findings of others, who demonstrated that SLC1A5 expression is associated with squamous cell histology . In an in vivo mice study, the glutamine tracer 5‐ 11 C‐(2S)‐glutamine ( 11 C‐Gln) uptake was higher in a squamous cell carcinoma than an adenocarcinoma, although n = 1 for both histologies, so the question is whether these tumors are a reliable representation of these histologies . However, we also examined GLS2 protein expression and mRNA expression of SLC1A5, GLS and GLS2.…”

Section: Discussioncontrasting

confidence: 61%

“…10,25,26 In an in vivo mice study, the glutamine tracer 5-11 C-(2S)-glutamine ( 11 C-Gln) uptake was higher in a squamous cell carcinoma than an adenocarcinoma, although n = 1 for both histologies, so the question is whether these tumors are a reliable representation of these histologies. 27 However, we also examined GLS2 protein expression and mRNA expression of SLC1A5, GLS and GLS2. All our findings indicate a higher glutamine consumption and metabolism in adenocarcinomas relative to squamous cell carcinomas.…”

Section: Nsclc Tumor Cell Metabolism In Relation To Histological Subtmentioning

confidence: 99%

See 1 more Smart Citation

Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes

et al. 2019

View full text Add to dashboard Cite

BackgroundBoth hypoxia and oncogenic mutations rewire tumor metabolism. In this study, glucose and glutamine metabolism‐related markers were examined in stage I ‐ resectable stage IIIA non‐small cell lung cancer (NSCLC). Furthermore, expression of metabolism‐related markers was correlated with mutational status to examine mutations associated with rewired tumor metabolism.MethodsMutation analysis was performed for 97 tumors. Glucose and glutamine metabolism‐related marker expression was measured by immunofluorescent staining (protein) and qPCR (mRNA) (n = 81).ResultsGlutamine metabolism‐related markers were significantly higher in adeno‐ than squamous cell NSCLCs. Glucose transporter 1 (GLUT1) protein expression was higher in solid compared to lepidic adenocarcinomas (P < 0.01). In adenocarcinomas, mRNA expression of glutamine transporter SLC1A5 correlated with tumor size (r(p) = 0.41, P = 0.005). Furthermore, SLC1A5 protein expression was significantly higher in adenocarcinomas with worse pTNM stage (r(s) = 0.39, P = 0.009). EGFR‐mutated tumors showed lower GLUT1 protein (P = 0.017), higher glutaminase 2 (GLS2) protein (P = 0.025) and higher GLS2 mRNA expression (P = 0.004), compared to EGFR wild‐type tumors. GLS mRNA expression was higher in KRAS‐mutated tumors (P = 0.019). TP53‐mutated tumors showed higher GLUT1 expression (P = 0.009).ConclusionsNSCLC is a heterogeneous disease, with differences in mutational status and metabolism‐related marker expression between adeno‐ and squamous cell NSCLCs, and also within adenocarcinoma subtypes. GLUT1 and SLC1A5 expression correlate with aggressive tumor behavior in adenocarcinomas but not in squamous cell NSCLCs. Therefore, these markers could steer treatment modification for subgroups of adenocarcinoma patients. TP53, EGFR and KRAS mutations are associated with expression of glucose and glutamine metabolism‐related markers in NSCLC.

show abstract

Section: Discussioncontrasting

confidence: 61%

Section: Nsclc Tumor Cell Metabolism In Relation To Histological Subtmentioning

confidence: 99%

Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The mechanism that drives the expression of isoforms are yet to be elucidated. Furthermore, our results emphasize the role of glucose and glutamine as anaplerotic nutrients that support the The results further substantiate previous elegant studies on the interactions between glucose and glutamine catabolism that support the survival of cancer cells [22][23][24][25] . This phenomenon is exemplified by the observed increase in glutamine catabolism upon inhibition of the mitochondrial pyruvate transporter 22 , or in response to a decreased rate of glycolysis when either mTOR or EGFR are targeted 24,25 .…”

Section: Discussionsupporting

confidence: 89%

“…However, the inability to reach a complete inhibition of tumourigenesis in any of these experiments suggests that tumours engage mechanisms of compensation that allow them to survive and proliferate despite decreased activity of these enzymes. Although the understanding of the complexity of factors determining tumour metabolic vulnerabilities and flexibilities is emerging 1,[22][23][24][25] , the mechanisms of metabolic resistance of tumours in vivo still remain largely unknown. Here M é n d e z -L u c a s A , e t a l 3 we have combined metabolomics, genomics and pharmacological approaches to demonstrate the high flexibility of tumour metabolism, and how blocking the mechanisms of compensation can lead to stronger inhibition of tumour growth in vivo.…”

Section: Introductionmentioning

confidence: 99%

Identifying strategies to target the metabolic flexibility of tumours

Méndez-Lucas

Lin

Driscoll

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryPlasticity of cancer metabolism can be a major obstacle for efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify and quantify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that glutaminase isoform Gls2, expressed in normal liver, compensates for the deletion of Gls1 isoform expressed in tumours. Inhibiting both glutaminases significantly delays tumourigenesis but does not completely block glutamine catabolism through the Krebs cycle. We reveal that glutamine catabolism is then driven by amidotransferases. Consistently, the synergistic effect of glutaminase and amidotransferase inhibitors on proliferation of mouse and human tumour cells is observed in vitro and in vivo. Furthermore, when Gls1 is deleted the Krebs cycle activity and tumour formation can also be significantly affected if glycolysis is co-inhibited (Gls1KO/Hk2KO). Finally, the inhibition of either serine (Psat1KO) or fatty acid (FasnKO) biosynthesis can be compensated by uptake of circulating nutrients. Thus, removing these nutrients from the diet produces synergistic effects on suppression of tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate how targeting compensatory mechanisms can improve a therapeutic outcome.

show abstract

“…Compared with lung ADCs, lung SCCs have higher levels of glucose metabolism to meet the anabolic and catabolic needs required to sustain rapid tumor growth (7). Hexokinases (HKs) catalyze the rate-limit and first committed step in glucose metabolism by phosphorylating glucose (8,9).…”

Section: Introductionmentioning

confidence: 99%

Hexokinase 2 Depletion Confers Sensitization to Metformin and Inhibits Glycolysis in Lung Squamous Cell Carcinoma

Guo

Kuang

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

Lung squamous cell carcinomas (SCCs) are highly aggressive tumors, and there is currently no effective targeted therapy owing to the lack of specific mutation targets. Compared with lung adenocarcinoma (ADCs), lung SCCs reportedly utilized higher levels of glucose metabolism to meet the anabolic and catabolic needs required to sustain rapid tumor growth. Hexokinase 2 (HK2) is an enzyme that catalyzes the rate-limit and first committed step in glucose metabolism. Here, we investigated the expression and effect of HK2 in lung SCCs. We found a significantly higher HK2 expression in lung SCCs, but not lung ADC or normal tissues. HK2 depletion or inhibition decreased the glycolysis and tumor growth via activating AMPK signaling pathway, which downregulated mTORC1 activity. Furthermore, we found an increased oxygen respiration rate compensating for HK2 depletion. Thus, metformin treatment showed combinatorial therapeutic value, which resulted in greater induction of lung SCC apoptosis in vitro and in vivo. Our study suggests that HK2 depletion in combination with metformin might be a novel effective strategy for lung SCCs therapy.

show abstract

The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma

Cited by 149 publications

References 42 publications

Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes

Glucose and glutamine metabolism in relation to mutational status in NSCLC histological subtypes

Identifying strategies to target the metabolic flexibility of tumours

Hexokinase 2 Depletion Confers Sensitization to Metformin and Inhibits Glycolysis in Lung Squamous Cell Carcinoma

Contact Info

Product

Resources

About