Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells

Chen, Pei Hsuan; Cai, Ling; Huffman, Kenneth E.; Yang, Chendong; Kim, Jiyeon; Faubert, Brandon; Boroughs, Lindsey K.; Ko, Bookyung; Sudderth, Jessica; McMillan, Elizabeth A.; Girard, Luc; Dong, Chen; Peyton, Michael; Shields, Morgan C.; Yao, Bo; Shames, David S.; Kim, Hyun‐Seok; Timmons, Brenda C.; Sekine, Ikuo; Britt, Rebecca; Weber, Stephanie; Byers, Lauren A.; Heymach, John V.; Chen, Jing; White, Michael A.; Minna, John D.; Xiao, Guanghua; DeBerardinis, Ralph J.

doi:10.1016/j.molcel.2019.08.028

Cited by 148 publications

(122 citation statements)

References 59 publications

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“…These results correlated with the heterogeneous metabolic phenotypes found in solid lung tumors in vivo (23). A-427 cells cultured under lactic acidosis and normoxia increased their growth rate, possibly supported by the increased expression of both the ubiquitously and the insulin-responsive glucose transporters (GLUT1 and GLUT4).…”

Section: Discussionsupporting

confidence: 73%

Lactic Acidosis in the Presence of Glucose Diminishes Warburg Effect in Lung Adenocarcinoma Cells

Prado-Garcı́a¹,

Campa-Higareda²,

Romero-García³

2020

Front. Oncol.

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Lactic acidosis (3 to 40 mM, pH < 6.9) is a condition found in solid tumors because tumor cells have a high rate of glucose consumption and lactate production even in the presence of oxygen; nevertheless, the microenvironment might still provide a sufficient glucose supply. Lactic acidosis has been proposed to shift metabolism from aerobic glycolysis toward oxidative phosphorylation (OXPHOS). We tested if lung tumor cells cultured under lactic acidosis shift their metabolism from glycolysis to OXPHOS by consuming extracellular lactate, increasing growth rate. We analyzed lung adenocarcinoma (A-549, A-427) cell lines and non-transformed fibroblast cells (MRC-5), which were cultured using RPMI-1640 medium initially containing lactate (2 mM) and glucose (10 mM), at pH 7.2 or 6.2 and oxygen tension 21% O 2 (normoxia) or 2% O 2 (hypoxia). We obtained growth curves, as well as glucose consumption and lactate production rates (measured during exponential growth) for each cell line. HIF-1α (Hypoxia-inducible factor 1 α), CS (citrate synthase) and AMPK (AMP-activated protein kinase) transcript levels were analyzed using RT-qPCR. By flow cytometry, we determined: (a) expression of glucose transporters (GLUT)1 and 4; (b) lactate transporters (MCT)1 and 4; (c) cell cycle profile, and (d) protein levels of HIF-1α, total and phosphorylated AMPK (pAMPK). Mitochondrial functionality was evaluated by measuring O 2 consumption in tumor cells using polarography and a Clark-type electrode. Tumor and non-transformed cells used both aerobic glycolysis and OXPHOS for obtaining energy. As of 48 h of culture, lactate levels ranged from (4.5-14 mM), thus forming a lactic environment. Lactic acidosis diminished GLUT1/GLUT4 expression and glucose consumption in A-549, but not in A-427 cells, and induced differential expression of HIF-1α, AMPK, and CS transcripts. A-427 cells increased pAMPK and HIF-1α levels and shifted their metabolism increasing OXPHOS; thus supporting cell growth. Conversely, A-549 cells increased HIF-1α protein levels, but did not activate AMPK and diminished OXPHOS. A-549 cells survived by arresting cells in G1-phase. Our findings show that lactic acidosis diminishes Warburg effect in tumor cells, but this change does not necessarily promote a shift to OXPHOS. Hence, lung adenocarcinomas show a differential metabolic response even when they are under the same microenvironmental conditions.

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Section: Discussionsupporting

confidence: 73%

Lactic Acidosis in the Presence of Glucose Diminishes Warburg Effect in Lung Adenocarcinoma Cells

Prado-Garcı́a¹,

Campa-Higareda²,

Romero-García³

2020

Front. Oncol.

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“…By using gene expression data, we have not accounted for these factors, and as such our analysis may not reflect pathway activity at the metabolic flux level. We expect that expanding recent efforts to characterize metabolite abundance (Li et al, 2019) and metabolite flux (Chen et al, 2019) in panels of cancer cell lines will improve our ability to identify metabolic pathway vulnerabilities by providing better measures of metabolic pathway activity.…”

Section: Discussionmentioning

confidence: 99%

The landscape of metabolic pathway dependencies in cancer cell lines

Joly

Chew

Graham

2020

Preprint

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The metabolic reprogramming of cancer cells creates metabolic vulnerabilities that can be therapeutically targeted. However, our understanding of metabolic dependencies and the pathway crosstalk that creates these vulnerabilities in cancer cells remains incomplete. Here, by integrating gene expression data with genetic loss-of-function and pharmacological screening data from hundreds of cancer cell lines, we identified metabolic vulnerabilities at the level of pathways rather than individual genes. This approach revealed that metabolic pathway dependencies are highly context-specific such cancer cells are vulnerable to inhibition of one metabolic pathway only when activity of another metabolic pathway is altered. Notably, we also found that the no single metabolic pathway was universally essential, suggesting that cancer cells are not invariably dependent on any metabolic pathway. In addition, we confirmed that cell culture medium is a major confounding factor for the analysis of metabolic pathway vulnerabilities. Nevertheless, we found robust associations between metabolic pathway activity and sensitivity to clinically approved drugs that were independent of cell culture medium. Lastly, we used parallel integration of pharmacological and genetic dependency data to confidently identify metabolic pathway vulnerabilities. Taken together, this study serves as a comprehensive characterization of the landscape of metabolic pathway vulnerabilities in cancer cell lines.

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“…Metabolic reprogramming is a characteristic hallmark in solid tumors (Chen et al, 2019; Satriano et al, 2019; Shukla et al, 2017; Tang, Su, Gu, & Rustgi, 2019; Tsegaye & Schafer, 2017; Ying et al, 2016; Yong et al, 2019; Yoshida, 2015). Other names for the same concept are metabolic rewiring or metabolic switching.…”

Section: Introductionmentioning

confidence: 99%

Redox tolerance and metabolic reprogramming in solid tumors

Mortezaee

2020

Cell Biology International

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Tumor cells need to cope with the host environment for survival and keep growing in hard conditions. This suggests that tumors must acquire characteristics more potent than what is seen for normal tissue cells, without which they are condemned to disruption. For example, cancer cells have more potent redox tolerance compared with normal cells, which is due to their high adaptation to an oxidative crisis. In addition, increased demand for bioenergetics and biosynthesis can cause a rise in nutrient uptake in tumors. Utilizing nutrients in low nutrient conditions suggests that tumors are also equipped with adaptive metabolic processes. Switching the metabolic demands toward glucose consumption upon exposure to the hypoxic tumor microenvironment, or changing toward using other sources when there is an overconsumption of glucose in the tumor area are examples of fitness metabolic systems in tumors. In fact, cancer cells in cooperation with their nearby stroma (in a process called metabolic coupling) can reprogram their metabolic systems in their favor. This suggests the high importance of stroma for meeting the metabolic demands of a growing tumor, an example in this context is the metabolic symbiosis between cancer‐associated fibroblasts with cancer cells. The point is that redox tolerance and metabolic reprogramming are interrelated, and that, without a doubt, disruption of redox tolerance systems by transient exposure to either oxidative or antioxidative loading, or targeting metabolic rewiring by modulation of tumor glucose availability, controlling tumor/stroma interactions, etc. can be effective from a therapeutic standpoint

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Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells

Cited by 148 publications

References 59 publications

Lactic Acidosis in the Presence of Glucose Diminishes Warburg Effect in Lung Adenocarcinoma Cells

Lactic Acidosis in the Presence of Glucose Diminishes Warburg Effect in Lung Adenocarcinoma Cells

The landscape of metabolic pathway dependencies in cancer cell lines

Redox tolerance and metabolic reprogramming in solid tumors

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