bims-meluca 2020-04-12 papers

Genes Dev. 2020 Apr 09.

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors.

Shuxi Qiao, Siang-Boon Koh, Varunika Vivekanandan, Devika Salunke, Krushna Chandra Patra, Elma Zaganjor, Kenneth Ross, Yusuke Mizukami, Sarah Jeanfavre, Athena Chen, Mari Mino-Kenudson, Sridhar Ramaswamy, Clary Clish, Marcia Haigis, Nabeel Bardeesy, Leif W Ellisen.

Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS mutant cells exhibit enhanced uptake of lysophospholipids and lipid storage, coupled to augmented fatty acid oxidation that sustains both ATP levels and ROS-detoxifying NADPH. Mechanistically, REDD1 loss triggers HIF-dependent activation of a lipid storage pathway involving PPARγ and the prometastatic factor CD36. Correspondingly, decreased REDD1 expression and a signature of REDD1 loss predict poor outcomes selectively in RAS mutant but not RAS wild-type human lung and pancreas carcinomas. Collectively, our findings reveal the REDD1-mediated stress response as a novel tumor suppressor whose loss defines a RAS mutant tumor subset characterized by reprogramming of lipid metabolism, invasive and metastatic progression, and poor prognosis. This work thus provides new mechanistic and clinically relevant insights into the phenotypic heterogeneity and metabolic rewiring that underlies these common cancers.

Keywords: RAS; REDD1; energy stress; fatty acid oxidation; glycolysis; lipid metabolism; lysophospholipids; metastasis; oxidative stress

DOI: https://doi.org/10.1101/gad.335166.119

Carcinogenesis. 2020 Apr 07. pii: bgaa036. [Epub ahead of print]

BAI1 acts as a tumor suppressor in lung cancer A549 cells by inducing metabolic reprogramming via the SCD1/HMGCR module.

Lei Liu, Li Chai, Jingjing Ran, Ying Yang, Li Zhang.

Brain angiogenesis inhibitor 1 (BAI1) is an important tumor suppressor in multiple cancers. However, the mechanisms behind its anti-tumor activity, particularly the relationship between BAI1 and metabolic aberrant of a tumor, remained unveiled. This study aimed to investigate whether BAI1 could inhibit biological functions in lung cancer A549 cells and the critical regulating molecules that induce metabolic reprogramming. Immunohistochemistry staining was performed to analyze whether variations in the expression of BAI1 in tumor tissues contributes to poor prognosis of lung cancer. Overexpressed BAI1 (BAI1-OE-A549) and control (Vector-NC-A549) were generated by lentiviral transfection. Biological function assays (proliferation, apoptosis, colony formation, invasion and in vivo metastasis), as well as metabolic reprogramming (by the Warburg effect and the glycolytic rate), were performed in both groups. Our results indicated that lower levels of BAI1 contributed to poor prognosis of lung cancer patients. Furthermore, overexpressed of BAI1 dramatically inhibited proliferation, migration, invasion, colony formation, and in vivo metastasis of A549 cells. The Warburg effect and the Seahorse assay revealed that BAI1-OE induced metabolism reprogramming by inhibiting the Warburg effect and glycolysis. Further exploration indicated that BAI1 induced metabolic reprogramming by upregulating stearoyl-CoA desaturase 1 (SCD1) and inhibited 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Our study revealed a novel mechanism through which BAI1 acted as tumor-suppressor by inducing metabolic reprogramming via the SCD1 and HMGCR module.

DOI: https://doi.org/10.1093/carcin/bgaa036

Front Pharmacol. 2019 ;10 1670

Searching for Drug Synergy Against Cancer Through Polyamine Metabolism Impairment: Insight Into the Metabolic Effect of Indomethacin on Lung Cancer Cells.

Freddy López-Contreras, Matías Muñoz-Uribe, Jorge Pérez-Laines, Laura Ascencio-Leal, Andrés Rivera-Dictter, Antonia Martin-Martin, Rafael A Burgos, Pablo Alarcon, Rodrigo López-Muñoz.

Non-small cell lung cancer (NSCLC) is the most lethal and prevalent type of lung cancer. In almost all types of cancer, the levels of polyamines (putrescine, spermidine, and spermine) are increased, playing a pivotal role in tumor proliferation. Indomethacin, a non-steroidal anti-inflammatory drug, increases the abundance of an enzyme termed spermidine/spermine-N1-acetyltransferase (SSAT) encoded by the SAT1 gene. This enzyme is a key player in the export of polyamines from the cell. The aim of this study was to compare the effect of indomethacin on two NSCLC cell lines, and their combinatory potential with polyamine-inhibitor drugs in NSCLC cell lines. A549 and H1299 NSCLC cells were exposed to indomethacin and evaluations included SAT1 expression, SSAT levels, and the metabolic status of cells. Moreover, the difference in polyamine synthesis enzymes among these cell lines as well as the synergistic effect of indomethacin and chemical inhibitors of the polyamine pathway enzymes on cell viability were investigated. Indomethacin increased the expression of SAT1 and levels of SSAT in both cell lines. In A549 cells, it significantly reduced the levels of putrescine and spermidine. However, in H1299 cells, the impact of treatment on the polyamine pathway was insignificant. Also, the metabolic features upstream of the polyamine pathway (i.e., ornithine and methionine) were increased. In A549 cells, the increase of ornithine correlated with the increase of several metabolites involved in the urea cycle. Evaluation of the levels of the polyamine synthesis enzymes showed that ornithine decarboxylase is increased in A549 cells, whereas S-adenosylmethionine-decarboxylase and polyamine oxidase are increased in H1299 cells. This observation correlated with relative resistance to polyamine synthesis inhibitors eflornithine and SAM486 (inhibitors of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase, respectively), and MDL72527 (inhibitor of polyamine oxidase and spermine oxidase). Finally, indomethacin demonstrated a synergistic effect with MDL72527 in A549 cells and SAM486 in H1299 cells. Collectively, these results indicate that indomethacin alters polyamine metabolism in NSCLC cells and enhances the effect of polyamine synthesis inhibitors, such as MDL72527 or SAM486. However, this effect varies depending on the basal metabolic fingerprint of each type of cancer cell.

Keywords: indomethacin; metabolism; non-small cell lung cancer; polyamine; spermidine/spermine-N1-acetyltransferase

DOI: https://doi.org/10.3389/fphar.2019.01670

J Oncol. 2020 ;2020 6249829

Pathological Mechanistic Studies of Osimertinib Resistance in Non-Small-Cell Lung Cancer Cells Using an Integrative Metabolomics-Proteomics Analysis.

Qing Ma, Jing Wang, Yaoyao Ren, Fanlu Meng, Lili Zeng.

Background: Osimertinib is the first-line therapeutic option for the T790M-mutant non-small-cell lung cancer and the acquired resistance obstructs its application. It is an urgent challenge to identify the potential mechanisms of osimertinib resistance for uncovering some novel therapeutic approaches.
Methods: In the current study, the cell metabolomics based on ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry and the qualitative and tandem mass tags quantitative proteomics were performed.
Results: 54 differential metabolites and 195 differentially expressed proteins were, respectively, identified. The amino acids metabolisms were significantly altered. HIF-1 signaling pathway modulating P-glycoproteins expression, PI3K-Akt pathway regulating survivin expression, and oxidative phosphorylation were upregulated, while arginine and proline metabolism regulating NO production and glycolysis/gluconeogenesis were downregulated during osimertinib resistance.
Conclusion: The regulation of HIF-1 and PI3K-Akt signaling pathway, energy supply process, and amino acids metabolism are the promising therapeutic tactics for osimertinib resistance.

DOI: https://doi.org/10.1155/2020/6249829

Front Oncol. 2020 ;10 276

Amino Acid Oncometabolism and Immunomodulation of the Tumor Microenvironment in Lung Cancer.

Johannes F Fahrmann, Jody V Vykoukal, Edwin J Ostrin.

The observation that cancer acquires significant changes in its metabolism dates back nearly a century, to Otto Warburg noting that cancer cells preferentially utilize glycolysis even when there are no hypoxic conditions in the growth media. Altered energetics are thus considered a hallmark of cancer. However, it has become clear that altered metabolism is not limited to cellular energetic pathways. Alterations in amino acid synthesis and catabolism, lipid biogenesis, and other pathways such as polyamine processing are commonly seen in cancer. Additionally, alterations in metabolism do not only have profound effects for cancer cells but also affect their surrounding microenvironment. With new cancer therapeutics targeting the immune microenvironment, these effects may have implications on cancer growth and response to therapy. These interactions are profound in lung cancer, further demonstrating the manifold interactions between developing tumors and the inflammatory microenvironment. Here, we discuss how dysregulation of metabolism in cancer alters its microenvironment and how this newfound knowledge can be exploited for anticancer treatment.

Keywords: arginine; asparagine; aspartate; glutamate; lung cancer; microenvironment; tryptophan

DOI: https://doi.org/10.3389/fonc.2020.00276

Oncology. 2020 Apr 06. 1-10

Polymorphisms in Glycolysis-Related Genes Are Associated with Clinical Outcomes of Paclitaxel-Cisplatin Chemotherapy in Non-Small Cell Lung Cancer.

Sun Ha Choi, Cheng Cheng Jin, Sook Kyung Do, Shin Yup Lee, Jin Eun Choi, Hyo-Gyoung Kang, Ji Hyun Kim, Jang Hyuck Lee, Mi Jeong Hong, Won Kee Lee, Ji Yun Jeong, Kyung Min Shin, Yong Hoon Lee, Hyewon Seo, Seung Soo Yoo, Jaehee Lee, Seung Ick Cha, Chang Ho Kim, Jae Yong Park.

OBJECTIVE: This study was conducted to investigate whether polymorphisms in glycolysis-related genes are associated with clinical outcomes of patients with advanced-stage non-small cell lung cancer (NSCLC) undergoing chemotherapy.
METHODS: A total of 377 patients with NSCLC were enrolled. Sixty-five single-nucleotide polymorphisms in 26 genes involved in the glycolytic pathway were evaluated. The associations of the variants with the chemotherapy response and overall survival (OS) were analyzed.
RESULTS: Among the 65 variants investigated, PFKL rs2073436C>G and GPI rs7248411C>G significantly correlated with clinical outcomes after chemotherapy in multivariate analyses. PFKL rs2073436C>G was significantly associated with both a worse response to chemotherapy (adjusted odds ratio [aOR] = 0.64, 95% CI = 0.45-0.90, p = 0.01) and a worse OS (adjusted hazard ratio [aHR] = 1.35, 95% CI = 1.14-1.61, p = 0.001). GPI rs7248411C>G was significantly associated with both a better chemotherapy response (aOR = 1.58, 95% CI = 1.07-2.23, p = 0.02) and a better OS (aHR = 0.80, 95% CI = 0.66-0.98, p = 0.03). When stratified by tumor histology, PFKL rs2073436C>G was significantly associated with OS only in squamous cell carcinoma, whereas GPI rs7248411C>G exhibited a significant association with the chemotherapy response and OS only in adenocarcinoma.
CONCLUSION: This result suggests that the PFKL rs2073436C>G and GPI rs7248411C>G are useful for predicting the clinical outcome of first-line paclitaxel-cisplatin chemotherapy in NSCLC.

Keywords: Chemotherapy response; Glycolysis; Lung cancer; Polymorphism; Survival

DOI: https://doi.org/10.1159/000504175