bims-meluca 2022-04-24 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–04–24
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

AKR1C1 promotes non-small cell lung cancer proliferation via crosstalk between HIF-1α and metabolic reprogramming.
A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers.
Leukemia inhibitory factor drives glucose metabolic reprogramming to promote breast tumorigenesis.
Anti-angiogenesis revisited: reshaping the treatment landscape of advanced non-small cell lung cancer.
A Hypoxia-Related Signature for Predicting Prognosis, Cellular Processes, Immune Microenvironment and Targeted Compounds in Lung Squamous Cell Carcinoma.
Expression of Serum sLOX-1 in Patients with Non-Small-Cell Lung Cancer and Its Correlation with Lipid Metabolism.
BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer.
Preclinical studies for improving radiosensitivity of non-small cell lung cancer cell lines by combining glutaminase inhibition and senolysis.

Transl Oncol. 2022 Apr 13. pii: S1936-5233(22)00081-X. [Epub ahead of print]20 101421

AKR1C1 promotes non-small cell lung cancer proliferation via crosstalk between HIF-1α and metabolic reprogramming.

Lin-Lin Chang, Pei-Hua Lu, Wei Yang, Yan Hu, Lin Zheng, Qiong Zhao, Neng-Ming Lin, Wen-Zhou Zhang.

  Non-small cell lung cancer (NSCLC) ranks first among cancer death worldwide. Despite efficacy and safety priority, targeted therapy only benefits ∼30% patients, leading to the unchanged survival rates for whole NSCLC patients. Metabolic reprogramming occurs to offer energy and intermediates for fuelling cancer cells proliferation. Thus, mechanistic insights into metabolic reprogramming may shed light upon NSCLC proliferation and find new proper targets for NSCLC treatment. Herein, we used loss- and gain-of-function experiments to uncover that highly expressed aldo-keto reductase family1 member C1 (AKR1C1) accelerated NSCLC cells proliferation via metabolic reprogramming. Further molecular profiling analyses demonstrated that AKR1C1 augmented the expression of hypoxia-inducible factor 1-alpha (HIF-1α), which could drive tumour metabolic reprogramming. What's more, AKR1C1 significantly correlated with HIF-1α signaling, which predicted poor prognosis for NSCLC patients. Collectively, our data display that AKR1C1 reprograms tumour metabolism to promote NSCLC cells proliferation by activating HIF-1α. These newly acquired data not only establish the specific role for AKR1C1 in metabolic reprogramming, but also hint to the possibility that AKR1C1 may be a new therapeutic target for NSCLC treatment.

Keywords:  AKR1C1; HIF-1α; Metabolic reprogramming; Proliferation

DOI:  https://doi.org/10.1016/j.tranon.2022.101421
Nat Commun. 2022 Apr 22. 13(1): 2206

A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers.

Pranavi Koppula, Guang Lei, Yilei Zhang, Yuelong Yan, Chao Mao, Lavanya Kondiparthi, Jiejun Shi, Xiaoguang Liu, Amber Horbath, Molina Das, Wei Li, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.

Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers.

DOI: https://doi.org/10.1038/s41467-022-29905-1
Cell Death Dis. 2022 Apr 19. 13(4): 370

Leukemia inhibitory factor drives glucose metabolic reprogramming to promote breast tumorigenesis.

Xuetian Yue, Jianming Wang, Chun-Yuan Chang, Juan Liu, Xue Yang, Fan Zhou, Xia Qiu, Vrushank Bhatt, Jessie Yanxiang Guo, Xiaoyang Su, Lanjing Zhang, Zhaohui Feng, Wenwei Hu.

LIF, a multifunctional cytokine, is frequently overexpressed in many types of solid tumors, including breast cancer, and plays an important role in promoting tumorigenesis. Currently, how LIF promotes tumorigenesis is not well-understood. Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression. However, the role of LIF in cancer metabolic reprogramming is unclear. In this study, we found that LIF increases glucose uptake and drives glycolysis, contributing to breast tumorigenesis. Blocking glucose uptake largely abolishes the promoting effect of LIF on breast tumorigenesis. Mechanistically, LIF overexpression enhances glucose uptake via activating the AKT/GLUT1 axis to promote glycolysis. Blocking the AKT signaling by shRNA or its inhibitors greatly inhibits glycolysis driven by LIF and largely abolishes the promoting effect of LIF on breast tumorigenesis. These results demonstrate an important role of LIF overexpression in glucose metabolism reprogramming in breast cancers, which contributes to breast tumorigenesis. This study also reveals an important mechanism underlying metabolic reprogramming of breast cancers, and identifies LIF and its downstream signaling as potential therapeutic targets for breast cancers, especially those with LIF overexpression.

DOI: https://doi.org/10.1038/s41419-022-04820-x
Arch Pharm Res. 2022 Apr 21.

Anti-angiogenesis revisited: reshaping the treatment landscape of advanced non-small cell lung cancer.

Sun Ha Choi, Seung Soo Yoo, Shin Yup Lee, Jae Yong Park.

  Although anti-angiogenic agents have been of limited use in the treatment of non-small cell lung cancer (NSCLC) until recently, further roles for the use of angiogenesis inhibition have emerged in the era of targeted therapy and immune checkpoint blockade. Given the shared common downstream signals of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) with their complementary roles in tumorigenesis and tumor angiogenesis, the dual inhibition of EGFR and VEGF pathways represents a rational strategy to maximize clinical efficacy and overcome resistance in the treatment of EGFR-mutant NSCLC. VEGF-driven angiogenesis is a potent driver of immunosuppressive tumor microenvironment (TME), with the recruited immunosuppressive cells driving angiogenesis, highlighting the interplay between the tumor vasculature and the anticancer immunity. Anti-angiogenic therapy can normalize the tumor vasculature and reprogram the TME from immunosuppressive into immunosupportive. Intensive research is under way to utilize the anti-angiogenic combination therapy to its full potential in diverse clinical settings in urgent unmet needs for the treatment of NSCLC. In this review, we present an overview of tumor angiogenesis and summarize the scientific background and preclinical and clinical evidence of anti-angiogenic therapy in combination with target therapy and immunotherapy for the treatment of NSCLC.

Keywords:  Angiogenesis; Anti-angiogenic therapy; Combination; Immunotherapy; Targeted therapy

DOI:  https://doi.org/10.1007/s12272-022-01382-6
Int J Gen Med. 2022 ;15 3991-4006

A Hypoxia-Related Signature for Predicting Prognosis, Cellular Processes, Immune Microenvironment and Targeted Compounds in Lung Squamous Cell Carcinoma.

Gujie Wu, Zhenyu Zhu, Zheng Yang, Min He, Kuan Ren, Yipeng Dong, Qun Xue.

   Background: Lung squamous cell carcinoma (LUSC) is a malignant tumour of the lung epithelium. A hypoxic environment can promote tumour cell proliferation and invasion. Therefore, this study aims to explore hypoxia-related genes and construct reliable models to predict the prognosis, cellular processes, immune microenvironment and target compounds of lung squamous carcinoma.
Methods: The transcriptome data and matched clinical information of LUSC were retrieved from The Cancer Genome Atlas (TCGA) database. The GSVA algorithm calculated each LUSC patient's hypoxia score, and all LUSC patients were divided into the high hypoxia score group and low hypoxia score group. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were performed to screen out differentially expressed hypoxia-related genes (DE-HRGs) in LUSC microenvironment, and the underlying regulatory mechanism of DE-HRGs in LUSC was explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Hereafter, we established a prognosis-related genetic signature for DE-HRGs using univariate and multivariate Cox regression analyses. The relationship between gene signature and immune cells was further evaluated. Finally, the Comparative Toxicogenomics Database (CTD) was utilized to predict the targeted drugs for the prognostic genes.
Results: We obtained 376 DE-HRGs. Functional enrichment analysis indicated that the DE-HRGs were involved in the cell cycle-related regulatory processes. Next, we developed and validated 3 HRGs-based prognostic signature for LUSC, including HELLS, GPRIN1, and FAM83A. Risk score is an independent prognostic factor for LUSC. Functional enrichment analysis and immune landscape analysis suggested that the risk scoring system might be involved in altering the immune microenvironment of LUSC patients to influence patient outcomes. Ultimately, a total of 92 potential compounds were predicted for the three prognostic genes.
Conclusion: In summary, we developed and validated a hypoxia-related model for LUSC, reflecting the cellular processes and immune microenvironment characteristics and predicting the prognostic outcomes and targeted compounds.

Keywords:  hypoxia; immune; lung squamous cell carcinoma; prognosis; targeted compounds

DOI:  https://doi.org/10.2147/IJGM.S344228
Can Respir J. 2022 ;2022 6619331

Expression of Serum sLOX-1 in Patients with Non-Small-Cell Lung Cancer and Its Correlation with Lipid Metabolism.

Fangfang Hao, Jinliang Chen, Jinnan Wu, Xin Ge, Xuedong Lv, Dongmei Zhang, Jianrong Chen.

Objective: The aim of this study was to investigate the expression level of soluble LOX-1 (sLOX-1) in the serum of non-small-cell lung cancer (NSCLC) patients and its correlation with lipid metabolism.
Methods: 99 inpatients with NSCLC and 81 healthy controls were enrolled in this study. The levels of serum sLOX-1 were compared between the two groups, and the correlation of sLOX-1 with clinicopathological characteristics, blood lipid indices, and carcinoembryonic antigen was analyzed.
Results: Compared with the healthy controls, sLOX-1, low-density lipoprotein, triglyceride, and carcinoembryonic antigen in the patients with NSCLC were significantly higher (p < 0.05), while the expression level of high-density lipoprotein was lower (p < 0.05). The expression level of sLOX-1 in the serum of patients with healthy controls was positively correlated with low-density lipoprotein (r = 0.72, p < 0.05). The levels of sLOX-1 and low-density lipoprotein in the serum of patients with NSCLC were closely related to the lymph node metastasis, distant metastasis, and TNM stage (p < 0.05). Compared with a single index, when the sLOX-1 was combined with the CEA, its specificity increased significantly to 97.5% (AUC = 0.995, p < 0.01, 95% CI: 0.989-1.000).
Conclusion: sLOX-1 and low-density lipoprotein were overexpressed in the serum of patients with NSCLC, positively correlated, and closely related to the TNM stage and metastasis. This result suggested that lipid metabolic disorders may promote the progression of NSCLC through sLOX-1, which could be a potential serological marker with diagnostic value for NSCLC.

DOI: https://doi.org/10.1155/2022/6619331
Antioxidants (Basel). 2022 Mar 29. pii: 661. [Epub ahead of print]11(4):

BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer.

Yang Lv, Xiaotong Lv, Jiahui Zhang, Guozhen Cao, Changzhi Xu, Buchang Zhang, Wenchu Lin.

  Accumulating evidence has witnessed the Kelch-like ECH-associated protein 1(KEAP1)- nuclear factor (erythroid-derived 2)-like 2 (Nrf2) axis is the main regulatory factor of cell resistance to endogenous and exogenous oxidative assaults. However, there are few studies addressing the upstream regulatory factors of KEAP1. Herein, bioinformatic analysis suggests bromodomain-containing protein 4 (BRD4) as a potential top transcriptional regulator of KEAP1 in lung cancer. Using molecular and pharmacological approaches, we then discovered that BRD4 can directly bind to the promoter of KEAP1 to activate its transcription and down-regulate the stability of Nrf2 which in turn transcriptionally suppresses glucose-6-phosphate dehydrogenase (G6PD) in small cell lung cancer (SCLC), a highly proliferative and aggressive disease with limited treatment options. In addition, BRD4 could associate with the Nrf2 protein in a non-KEAP1-dependent manner to inhibit Nrf2 activity. Furthermore, simultaneous application of JQ1 and ATRA or RRx-001 yielded synergistic inhibition both in vitro and in vivo. These data suggest metabolic reprogramming by JQ1 treatment improves cell resistance to oxidative stress and might be a resistance mechanism to bromodomain and extra-terminal domain (BET) inhibition therapy. Altogether, our findings provide novel insight into the transcriptional regulatory network of BRD4 and KEAP1 and transcriptional regulation of the pentose phosphate pathway in SCLC.

Keywords:  BRD4; KEAP1; Nrf2; pentose phosphate pathway; small cell lung cancer

DOI:  https://doi.org/10.3390/antiox11040661
Transl Oncol. 2022 Apr 19. pii: S1936-5233(22)00090-0. [Epub ahead of print]21 101431

Preclinical studies for improving radiosensitivity of non-small cell lung cancer cell lines by combining glutaminase inhibition and senolysis.

Masaki Fujimoto, Ritsuko Higashiyama, Hironobu Yasui, Koya Yamashita, Osamu Inanami.

  Glutamine metabolism, known as glutaminolysis, is abnormally activated in many cancer cells with KRAS or BRAF mutations or active c-MYC. Glutaminolysis plays an important role in the proliferation of cancer cells with oncogenic mutations. In this study, we characterized radiation-induced cell death, which was enhanced by glutaminolysis inhibition in non-small cell lung cancer A549 and H460 cell lines with KRAS mutation. A clonogenic survival assay revealed that treatment with a glutaminase inhibitor, CB839, enhanced radiosensitivity. X-irradiation increased glutamate production, mitochondrial oxygen consumption, and ATP production, whereas CB839 treatment suppressed these effects. The data suggest that the enhancement of glutaminolysis-dependent energy metabolism for ATP production is important for survival after X-irradiation. Evaluation of the cell death phenotype revealed that glutaminolysis inhibitory treatment with CB839 or a low-glutamine medium significantly promoted the proliferation of β-galactosidase-positive and IL-6/IL-8 secretory cells among X-irradiated tumor cells, corresponding to an increase in the senescent cell population. Furthermore, treatment with ABT263, a Bcl-2 family inhibitor, transformed senescent cells into apoptotic cells. The findings suggest that combination treatment with a glutaminolysis inhibitor and a senolytic drug is useful for efficient radiotherapy.

Keywords:  Apoptosis; Glutaminolysis; Radiation; Senescence; Senolytic drug

DOI:  https://doi.org/10.1016/j.tranon.2022.101431