bims-meluca 2021-03-28 papers

Cancer Res. 2021 Mar 22. pii: canres.2870.2020. [Epub ahead of print]

Glut1 expression in tumor-associated neutrophils promotes lung cancer growth and resistance to radiotherapy.

Pierre-Benoit Ancey, Caroline Contat, Gael Boivin, Silvia Sabatino, Justine Pascual, Nadine Zangger, Jean Yannis Perentes, Solange Peters, E Dale Abel, David G Kirsch, Jeffrey C Rathmell, Marie-Catherine Vozenin, Etienne Meylan.

Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or anti-tumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify Glut1 as an essential glucose transporter for their tumor supportive behavior. Compared to normal neutrophils, Glut1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of Glut1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of Glut1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of Glut1 in TANs, which may affect their pro- versus anti-tumor behavior. These results also suggest targeting metabolic vulnerabilities to favor anti-tumor neutrophils.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-2870

Cancer Metab. 2021 Mar 26. 9(1): 14

A small-molecule pan-class I glucose transporter inhibitor reduces cancer cell proliferation in vitro and tumor growth in vivo by targeting glucose-based metabolism.

Pratik Shriwas, Dennis Roberts, Yunsheng Li, Liyi Wang, Yanrong Qian, Stephen Bergmeier, Jennifer Hines, Subhodip Adhicary, Corinne Nielsen, Xiaozhuo Chen.

BACKGROUND: Cancer cells drastically increase the uptake of glucose and glucose metabolism by overexpressing class I glucose transporters (GLUT1-4) to meet their energy and biomass synthesis needs and are very sensitive and vulnerable to glucose deprivation. Although targeting glucose uptake via GLUTs has been an attractive anticancer strategy, the relative anticancer efficacy of multi-GLUT targeting or single GLUT targeting is unclear. Here, we report DRB18, a synthetic small molecule, is a potent anticancer compound whose pan-class I GLUT inhibition is superior to single GLUT targeting.
METHODS: Glucose uptake and MTT/resazurin assays were used to measure DRB18's inhibitory activities of glucose transport and cell viability/proliferation in human lung cancer and other cancer cell lines. Four HEK293 cell lines expressing GLUT1-4 individually were used to determine the IC50 values of DRB18's inhibitory activity of glucose transport. Docking studies were performed to investigate the potential direct interaction of DRB18 with GLUT1-4. Metabolomics analysis was performed to identify metabolite changes in A549 lung cancer cells treated with DRB18. DRB18 was used to treat A549 tumor-bearing nude mice. The GLUT1 gene was knocked out to determine how the KO of the gene affected tumor growth.
RESULTS: DRB18 reduced glucose uptake mediated via each of GLUT1-4 with different IC50s, which match with the docking glidescores with a correlation coefficient of 0.858. Metabolomics analysis revealed that DRB18 altered energy-related metabolism in A549 cells by changing the abundance of metabolites in glucose-related pathways in vitro and in vivo. DRB18 eventually led to G1/S phase arrest and increased oxidative stress and necrotic cell death. IP injection of DRB18 in A549 tumor-bearing nude mice at 10 mg/kg body weight thrice a week led to a significant reduction in the tumor volume compared with mock-treated tumors. In contrast, the knockout of the GLUT1 gene did not reduce tumor volume.
CONCLUSIONS: DRB18 is a potent pan-class I GLUT inhibitor in vitro and in vivo in cancer cells. Mechanistically, it is likely to bind the outward open conformation of GLUT1-4, reducing tumor growth through inhibiting GLUT1-4-mediated glucose transport and metabolisms. Pan-class I GLUT inhibition is a better strategy than single GLUT targeting for inhibiting tumor growth.

Keywords: Anticancer therapeutics; Glycolysis; Metabolomics; TCA cycle; The Warburg effect; docking

DOI: https://doi.org/10.1186/s40170-021-00248-7

Minerva Endocrinol (Torino). 2021 Mar 16.

Metformin improves survival in patients with concurrent diabetes and small cell lung cancer: a meta-analysis.

Hua Fan, Shikun Bai, Xin Guan, Wen Ma, Yu Fu, Xuan Zhang, Lili Deng, Jing Tian.

OBJECTIVE: To compare survival outcome among the patients with concurrent small cell lung cancer (SCLC) and diabetes mellitus (DM) using metformin or without metformin.
METHODS: A systematic literature search for relevant studies up to Oct 2020 was conducted. Outcome of the included studies included overall survival (OS) or disease-free survival (DFS). HR values were pooled to estimate the effect of metformin on survival outcomes.
RESULTS: 6 studies with 539 participants with both SCLC and diabetes were included in the analysis. The patients with metformin usage had significantly longer OS and DFS than those without metformin usage [OS: HR=0.72 (0.53-0.98), p=0.04; DFS: HR= 0.59 (0.45-0.76), p<0.0001)]. The studies included were not significantly different in the two analyses by heterogeneity test. There was no obvious publication bias.
CONCLUSIONS: Metformin may improve survival among patients with concurrent SCLC and DM. Further investigations especially randomized control trials are warranted, especially among the patients who do not have diabetes.

DOI: https://doi.org/10.23736/S2724-6507.21.03289-2

Front Cell Dev Biol. 2020 ;8 620603

Exosomes Derived From Macrophages Enhance Aerobic Glycolysis and Chemoresistance in Lung Cancer by Stabilizing c-Myc via the Inhibition of NEDD4L.

Huan Wang, Lie Wang, Haiyan Pan, Yaona Wang, Miao Shi, Hang Yu, Chaoye Wang, Xinfu Pan, Zhijun Chen.

As one of the most common and lethal cancer, lung cancer severely threatens the health of human. It has been reported that tumor-associated macrophages promote initiation, progression, as well as chemoresistance in human cancers. However, the underneath molecular mechanism that drives chemoresistance in lung cancer is yet not fully characterized. In this article, we demonstrated that M2 macrophage-derived exosomes (MDE) is the key factor to promote cisplatin-resistance in lung cancer. MDE exhibited high expression level of several miRNA including miR-3679-5p. Mechanistically, miR-3679-5p was delivered to lung cancer cells by MDE, downregulating the expression of a known E3 ligase, NEDD4L, which has been identified as a key regulator controlling the stability of c-Myc. Such decreased NEDD4L expression level resulted in the stabilization of c-Myc and elevated glycolysis. The enhanced glycolysis drives the chemoresistance in lung cancer. Taken together, our findings not only show that M2 macrophage induce chemoresistance in lung cancer through MDE mediated miR-3679-5R/NEDD4L/c-Myc signaling cascade, but also shed the light on the mechanism of the cross-talk between M2 macrophage and lung cancers. By pinpointing a potential novel survival signaling pathway, our data could provide a new potential therapeutic target for lung cancer treatment and management.

Keywords: M2 macrophage-derived exosomes; NEDD4L; chemoresistance; glycolysis; lung cancer

DOI: https://doi.org/10.3389/fcell.2020.620603

Front Oncol. 2021 ;11 645821

Monoamine Oxidase A Inhibits Lung Adenocarcinoma Cell Proliferation by Abrogating Aerobic Glycolysis.

Yumin Huang, Wei Zhao, Xiaoping Ouyang, Feng Wu, Yujian Tao, Minhua Shi.

Lung adenocarcinoma (LUAD) accounts for ~30% of all lung cancers and is one of the causes of cancer-related death worldwide. As the role of monoamine oxidase A (MAOA) in LUAD remains unclear, in this study, we examine how MAOA affects LUAD cell proliferation. Analyses of both public data and our data reveal that the expression of MAOA is downregulated in LUAD compared with non-tumor tissue. In addition, the expression of MAOA in tumors correlates with clinicopathologic features, and the expression of MAOA serves as an independent biomarker in LUAD. In addition, the overexpression of MAOA inhibits LUAD cell proliferation by inducing G1 arrest in vitro. Further mechanistic studies show that MAOA abrogates aerobic glycolysis in LUAD cells by decreasing hexokinase 2 (HK2). Finally, the expression of HK2 shows a negative correlation with MAOA in LUAD, and high HK2 predicts poor clinical outcome. In conclusion, our findings indicate that MAOA functions as a tumor suppressor in LUAD. Our results indicate that the MAOA/HK2 axis could be potential targets in LUAD therapy.

Keywords: aerobic glycolysis; cell prolferation; hexokinase 2; lung adenocarcinoma; monoamine oxidase A

DOI: https://doi.org/10.3389/fonc.2021.645821

J Transl Med. 2021 Mar 21. 19(1): 118

GRP78 in lung cancer.

Shengkai Xia, Wenzhe Duan, Wenwen Liu, Xinri Zhang, Qi Wang.

Glucose-regulating protein 78 (GRP78) is a molecular chaperone in the endoplasmic reticulum (ER) that promotes folding and assembly of proteins, controls the quality of proteins, and regulates ER stress signaling through Ca2+ binding to the ER. In tumors, GRP78 is often upregulated, acting as a central stress sensor that senses and adapts to changes in the tumor microenvironment, mediating ER stress of cancer cells under various stimulations of the microenvironment to trigger the folding protein response. Increasing evidence has shown that GRP78 is closely associated with the progression and poor prognosis of lung cancer, and plays an important role in the treatment of lung cancer. Herein, we reviewed for the first time the functions and mechanisms of GRP78 in the pathological processes of lung cancer, including tumorigenesis, apoptosis, autophagy, progression, and drug resistance, giving a comprehensive understanding of the function of GRP78 in lung cancer. In addition, we also discussed the potential role of GRP78 as a prognostic biomarker and therapeutic target for lung cancer, which is conducive to improving the assessment of lung cancer and the development of new therapeutic interventions.

Keywords: Autophagy; Endoplasmic reticulum; GRP78; Lung cancer; Unfolded protein response (UPR)

DOI: https://doi.org/10.1186/s12967-021-02786-6