bims-meluca 2021-08-01 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–08–01
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

Potential therapeutics using tumor-secreted lactate in nonsmall cell lung cancer.
The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.
The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth.
Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer.
Vitamin D affects the Warburg effect and stemness maintenance of non-small-cell lung cancer cells by regulating PI3K/AKT/mTOR signaling pathway.
Relationship between glucosamine use and the risk of lung cancer: data from a nationwide prospective cohort study.
KEAP1/NRF2 (NFE2L2) mutations in NSCLC - Fuel for a superresistant phenotype?
Fascin promotes lung cancer growth and metastasis by enhancing glycolysis and PFKFB3 expression.

Drug Discov Today. 2021 Jul 26. pii: S1359-6446(21)00322-6. [Epub ahead of print]

Potential therapeutics using tumor-secreted lactate in nonsmall cell lung cancer.

Zi-Xian Liao, Ivan M Kempson, Chia-Chen Hsieh, S-Ja Tseng, Pan-Chyr Yang.

  Targeted-therapy failure in treating nonsmall cell lung cancer (NSCLC) frequently occurs because of the emergence of drug resistance and genetic mutations. The same mutations also result in aerobic glycolysis, which further antagonizes outcomes by localized increases in lactate, an immune suppressor. Recent evidence indicates that enzymatic lowering of lactate can promote an oncolytic immune microenvironment within the tumour. Here, we review factors relating to lactate expression in NSCLC and the utility of lactate oxidase (LOX) for governing therapeutic delivery, its role in lactate oxidation and turnover, and relationships between lactate depletion and immune cell populations. The lactate-rich characteristic of NSCLC provides an exploitable property to potentially improve NSCLC outcomes and design new therapeutic strategies to integrate with conventional therapies.

Keywords:  NSCLC; Nanoparticles; lactate; lactate oxidase; non-small cell lung cancer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.drudis.2021.07.014
Nat Commun. 2021 Jul 30. 12(1): 4651

The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.

Nour Ghaddar, Shuo Wang, Bethany Woodvine, Jothilatha Krishnamoorthy, Vincent van Hoef, Cedric Darini, Urszula Kazimierczak, Nicolas Ah-Son, Helmuth Popper, Myriam Johnson, Leah Officer, Ana Teodósio, Massimo Broggini, Koren K Mann, Maria Hatzoglou, Ivan Topisirovic, Ola Larsson, John Le Quesne, Antonis E Koromilas.

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.

DOI: https://doi.org/10.1038/s41467-021-24661-0
Cell Death Dis. 2021 Jul 29. 12(8): 751

The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth.

Tong Zhou, Yong-Hua Sang, Shang Cai, Chun Xu, Min-Hua Shi.

POLRMT (RNA polymerase mitochondrial) is responsible for the transcription of mitochondrial genome encoding key components of oxidative phosphorylation. This process is important for cancer cell growth. The current study tested expression and potential functions of POLRMT in non-small cell lung cancer (NSCLC). TCGA cohorts and the results from the local lung cancer tissues showed that POLRMT is overexpressed in human lung cancer tissues. In both primary human NSCLC cells and A549 cells, POLRMT silencing (by targeted lentiviral shRNAs) or knockout (through CRSIPR/Cas9 gene editing method) potently inhibited cell viability, proliferation, migration, and invasion, and induced apoptosis activation. On the contrast, ectopic overexpression of POLRMT using a lentiviral construct accelerated cell proliferation and migration in NSCLC cells. The mtDNA contents, mRNA levels of mitochondrial transcripts, and subunits of respiratory chain complexes, as well as S6 phosphorylation, were decreased in POLRMT-silenced or -knockout NSCLC cells, but increased after ectopic POLRMT overexpression. In vivo, intratumoral injection of POLRMT shRNA adeno-associated virus (AAV) potently inhibited NSCLC xenograft growth in severe combined immune deficiency mice. The mtDNA contents, mRNA levels of mitochondria respiratory chain complex subunits, and S6 phosphorylation were decreased in POLRMT shRNA AAV-injected NSCLC xenograft tissues. These results show that POLRMT is a novel and important oncogene required for NSCLC cell growth in vitro and in vivo.

DOI: https://doi.org/10.1038/s41419-021-04039-2
Cell Death Dis. 2021 Jul 27. 12(8): 741

Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer.

Danielle S Potter, Ruochen Du, Patrick Bhola, Raphael Bueno, Anthony Letai.

Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.

DOI: https://doi.org/10.1038/s41419-021-04029-4
Curr Cancer Drug Targets. 2021 Jul 28.

Vitamin D affects the Warburg effect and stemness maintenance of non-small-cell lung cancer cells by regulating PI3K/AKT/mTOR signaling pathway.

Yiyan Song Yang, Songyisha Yang, Dejia Li, Wen Li.

   BACKGROUND: Non-small-cell lung cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of all lung cancer cases and resulting in high morbidity and mortality. Previous studies have demonstrated that 1,25-dihydroxy-vitamin-D3 (vitamin D) exhibited anti-cancer activity against breast and prostate cancer.
OBJECTIVES: The aim of the current study is to investigate the effect of vitamin D on NSCLC and its underlying mechanism.
METHODS: The effects of vitamin D on stemness maintenance and the Warburg effect in NSCLC cells were investigated both in vitro and in vivo.
RESULTS & DISCUSSION: In vitro experiments revealed that vitamin D inhibited glycolysis and stemness maintenance in A549 and NCI-H1975 cells. Both in vitro and in vivo experiments indicated that vitamin D attenuated the expression of metabolism-related enzymes associated with the Warburg effect (GLUT1, LDHA, HK2, and PKM2). In addition, vitamin D down-regulated the expression of stemness-related genes (Oct-4, SOX-2, and Nanog) and the expression of PI3K, AKT, and mTOR.
CONCLUSION: Overall, these findings suggest that vitamin D suppresses the Warburg effect and stemness maintenance in NSCLC cells via the inactivation of PI3K/AKT/mTOR signaling, thereby inhibiting the progression of NSCLC. The current study indicates that vitamin D is a potential candidate in therapeutic strategies against NSCLC.

Keywords:  1; 25-dihydroxy-vitamin-D3; Cancer stem cell; Non-small cell lung cancer; PI3K/AKT/mTOR; Warburg effect; stemness maintenance

DOI:  https://doi.org/10.2174/1568009621666210729100300
Eur Respir J. 2021 Jul 29. pii: 2101399. [Epub ahead of print]

Relationship between glucosamine use and the risk of lung cancer: data from a nationwide prospective cohort study.

Guowei Li, Xuhui Zhang, Yingxin Liu, Junguo Zhang, Likang Li, Xin Huang, Lehana Thabane, Gregory Y H Lip.

BACKGROUND: Research on glucosamine shows anti-inflammatory and anti-cancer benefits with a minimal adverse effects. We aimed to explore the relationship between use of glucosamine and risk of lung cancer and lung cancer mortality based on data from the large-scale nationwide prospective UK Biobank cohort study.
METHODS: Participants were enrolled between the year 2006 and 2010 and followed up to 2020. Cox proportion hazards model were used to assess the relationship between glucosamine use and risk of lung cancer and lung cancer mortality. Subgroup analyses and sensitivity analyses were performed to explore the potential effect modifications and the robustness of main findings.
RESULTS: A total of 439,393 participants (mean age: 56 years; 53% females) with a mean follow-up of 11 years were included for analyses. There were 82,603 (18.80%) participants reporting regular use of glucosamine at baseline. During follow-up, there were 1,971 (0.45%) lung cancer events documented. Glucosamine use was significantly associated with a decreased risk of lung cancer (hazard ratio=0.84, 95% CI: 0.75-0.92, p<0.001) and lung cancer mortality (hazard ratio=0.88, 95% CI: 0.81-0.96, p=0.002) in fully-adjusted models. A stronger association between glucosamine use and decreased lung cancer risk was observed in participants with a family history of lung cancer when compared to those without a family history.
CONCLUSION: Regular use of glucosamine was significantly related with decreased risk of lung cancer and lung cancer mortality, based on data from this nationwide prospective cohort study.

DOI: https://doi.org/10.1183/13993003.01399-2021
Lung Cancer. 2021 Jul 17. pii: S0169-5002(21)00469-4. [Epub ahead of print]159 10-17

KEAP1/NRF2 (NFE2L2) mutations in NSCLC - Fuel for a superresistant phenotype?

Wolfram C M Dempke, Martin Reck.

  The transcription factor NRF2 (nuclear factor E2-related factor 2) (also known as nuclear factor, erythroid 2 like 2 [NFE2L2]) is the master regulator of cellular antioxidant responses. NRF2 is repressed by interaction with a redox-sensitive protein KEAP1 (Kelch-like ECH-associated protein 1). Dysregulation of KEAP1/NRF2 transcriptional activity has been associated with the pathogenesis of multiple diseases, and the KEAP1/NRF2 axis has emerged to be the most important modulator of cellular homeostasis. Oxidative stress plays an important role in the initiation and progression of many chronic diseases, including diabetes, cancer, and neurodegenerative diseases. Although its role in immunotherapy is still somewhat controversial, it is well documented from clinical studies that KEAP1/NRF2 mutations in NSCLCs are associated with resistance to various cancer treatments including chemotherapy, X-irradiation, TKI treatment, and a shorter OS and currently available results from clinical trials suggest that KEAP1/NRF2 mutations can be used as a prognostic biomarker (poorer prognosis) for determining prognosis following immunotherapy and a predictive marker for chemo-, radio-, immunotherapy- and TKI-resistance. Despite overwhelming enthusiasm about the various KEAP1/NRF2 inhibitors that have been described during the last decades, none of these inhibitors are currently explored in clinical trials or in clinical applications which clearly add weight to the proposal that the development of these inhibitors remains challenging, but will be beneficial for novel treatment approaches in NSCLC in the near future. In this review we highlight the molecular features, the key components, and possible inhibitors of the KEAP1/NRF2 pathway, its role as prognostic and predictive biomarker, and the resulting clinical implications in NSCLC patients.

Keywords:  Clinical studies; Inhibitors; KEAP1/NRF2 (NFE2L2) mutations; NSCLC; Prognostic and predictive factors

DOI:  https://doi.org/10.1016/j.lungcan.2021.07.006
Cancer Lett. 2021 Jul 22. pii: S0304-3835(21)00352-9. [Epub ahead of print]518 230-242

Fascin promotes lung cancer growth and metastasis by enhancing glycolysis and PFKFB3 expression.

Shengchen Lin, Yunzhan Li, Dezhen Wang, Chongbiao Huang, David Marino, Oana Bollt, Chaodong Wu, Matthew D Taylor, Wei Li, Gina M DeNicola, Jihui Hao, Pankaj K Singh, Shengyu Yang.

  Fascin is a pro-metastatic actin-bundling protein that is upregulated in all metastatic carcinomas. Fascin promotes cancer cell migration and invasion by facilitating membrane protrusions, such as filopodia and invadopodia. Aerobic glycolysis is a key feature of cancer metabolism and provides critical intermediate metabolites for tumor growth. Here, we report that fascin increases glycolysis in lung cancer to promote tumor growth and metastasis. Fascin promotes glycolytic flux by increasing the expression and activities of phosphofructose-kinases 1 and 2 (PFK1 and 2). Fascin mediates glycolytic functions via activation of yes-associated protein 1 (YAP1) through its canonical actin-bundling activity by promoting the binding of YAP1 to a TEAD1/4 binding motif located 30 bp upstream of the PFKFB3 transcription start site to activate its transcription. Examination of the TCGA database suggests that the fascin-YAP1-PFKFB3 axis is likely conserved across different types of cancers. Importantly, pharmacological inhibitors of fascin suppressed YAP1-PFKFB3 signaling and glycolysis in cancer cell lines, organoid cultures, and xenograft metastasis models. Taken together, our data reveal that the glycolytic function of fascin is essential for the promotion of lung cancer growth and metabolism, and suggest that pharmacological inhibitors of fascin may be used to reprogram cancer metabolism in lung and potentially other cancers with fascin upregulation.

Keywords:  Fascin inhibitor; Metabolism; YAP1

DOI:  https://doi.org/10.1016/j.canlet.2021.07.025