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

2020 ◽  
Author(s):  
Lei Liu ◽  
Li Chai ◽  
Jingjing Ran ◽  
Ying Yang ◽  
Li Zhang
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Colony Formation ◽  
Warburg Effect ◽  
Poor Prognosis ◽  
A549 Cells ◽  
Angiogenesis Inhibitor ◽  
Metabolic Reprogramming ◽  
The Warburg Effect

Abstract Brain-specific 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.

scholarly journals O-GlcNAcylation destabilizes the active tetrameric PKM2 to promote the Warburg effect

2017 ◽  
Vol 114 (52) ◽  
pp. 13732-13737 ◽  
Author(s):  
Yang Wang ◽  
Jia Liu ◽  
Xin Jin ◽  
Dapeng Zhang ◽  
Dongxue Li ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Nuclear Translocation ◽  
Lactate Production ◽  
Human Tumor ◽  
Glucose Consumption ◽  
Metabolic Reprogramming ◽  
Proliferating Cells ◽  
The Warburg Effect

The Warburg effect, characterized by increased glucose uptake and lactate production, is a well-known universal across cancer cells and other proliferating cells. PKM2, a splice isoform of the pyruvate kinase (PK) specifically expressed in these cells, serves as a major regulator of this metabolic reprogramming with an adjustable activity subjected to numerous allosteric effectors and posttranslational modifications. Here, we have identified a posttranslational modification on PKM2, O-GlcNAcylation, which specifically targets Thr405 and Ser406, residues of the region encoded by the alternatively spliced exon 10 in cancer cells. We show that PKM2 O-GlcNAcylation is up-regulated in various types of human tumor cells and patient tumor tissues. The modification destabilized the active tetrameric PKM2, reduced PK activity, and led to nuclear translocation of PKM2. We also observed that the modification was associated with an increased glucose consumption and lactate production and enhanced level of lipid and DNA synthesis, indicating that O-GlcNAcylation promotes the Warburg effect. In vivo experiments showed that blocking PKM2 O-GlcNAcylation attenuated tumor growth. Thus, we demonstrate that O-GlcNAcylation is a regulatory mechanism for PKM2 in cancer cells and serves as a bridge between PKM2 and metabolic reprogramming typical of the Warburg effect.

scholarly journals In vivo genetic dissection of tumor growth and the Warburg effect

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Cheng-Wei Wang ◽  
Arunima Purkayastha ◽  
Kevin T Jones ◽  
Shivani K Thaker ◽  
Utpal Banerjee
Keyword(s):  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Feedback Signal ◽  
Vegf Receptor ◽  
Genetic Dissection ◽  
Oncogenic Pathways ◽  
Genes Encoding ◽  
The Warburg Effect

A well-characterized metabolic landmark for aggressive cancers is the reprogramming from oxidative phosphorylation to aerobic glycolysis, referred to as the Warburg effect. Models mimicking this process are often incomplete due to genetic complexities of tumors and cell lines containing unmapped collaborating mutations. In order to establish a system where individual components of oncogenic signals and metabolic pathways can be readily elucidated, we induced a glycolytic tumor in the Drosophila wing imaginal disc by activating the oncogene PDGF/VEGF-receptor (Pvr). This causes activation of multiple oncogenic pathways including Ras, PI3K/Akt, Raf/ERK, Src and JNK. Together this network of genes stabilizes Hifα (Sima) that in turn, transcriptionally up-regulates many genes encoding glycolytic enzymes. Collectively, this network of genes also causes inhibition of pyruvate dehydrogenase (PDH) activity resulting in diminished ox-phos levels. The high ROS produced during this process functions as a feedback signal to consolidate this metabolic reprogramming.

scholarly journals Tumor suppressor SMAR1 regulates PKM alternative splicing by HDAC6-mediated deacetylation of PTBP1

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Arpankumar Choksi ◽  
Apoorva Parulekar ◽  
Richa Pant ◽  
Vibhuti Kumar Shah ◽  
Ramakrishna Nimma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Alternative Splicing ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Dependent Manner ◽  
Alternative Splicing Events ◽  
Isoform Expression ◽  
The Warburg Effect

Abstract Background Highly proliferating cancer cells exhibit the Warburg effect by regulation of PKM alternative splicing and promoting the expression of PKM2. Majority of the alternative splicing events are known to occur in the nuclear matrix where various MARBPs actively participate in the alternative splicing events. SMAR1, being a MARBP and an important tumor suppressor, is known to regulate the splicing of various cancer-associated genes. This study focuses on the regulation of PKM alternative splicing and inhibition of the Warburg effect by SMAR1. Methods Immunohistochemistry was performed in breast cancer patient samples to establish the correlation between SMAR1 and PKM isoform expression. Further, expression of PKM isoforms upon modulation in SMAR1 expression in breast cancer cell lines was quantified by qRT-PCR and western blot. The acetylation status of PTBP1 was estimated by immunoprecipitation along with its enrichment on PKM pre-mRNA by CLIP in SMAR1 knockdown conditions. The role of SMAR1 in tumor metabolism and tumorigenesis was explored by in vitro enzymatic assays and functional assays upon SMAR1 knockdown. Besides, in vivo tumor formation by injecting adeno-SMAR1-transduced MDA-MB-231 cells in NOD/SCID mice was performed. Results The expression profile of SMAR1 and PKM isoforms in breast cancer patients revealed that SMAR1 has an inverse correlation with PKM2 and a positive correlation with PKM1. Further quantitative PKM isoform expression upon modulation in SMAR1 expression also reflects that SMAR1 promotes the expression of PKM1 over tumorigenic isoform PKM2. SMAR1 deacetylates PTBP1 via recruitment of HDAC6 resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. SMAR1 inhibits the Warburg effect, tumorigenic potential of cancer cells, and in vivo tumor generation in a PKM2-dependent manner. Conclusions SMAR1 regulates PKM alternative splicing by causing HDAC6-dependent deacetylation of PTBP1, resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. Additionally, SMAR1 suppresses glucose utilization and lactate production via repression of PKM2 expression. This suggests that tumor suppressor SMAR1 inhibits tumor cell metabolism and tumorigenic properties of cancer cells via regulation of PKM alternative splicing.

scholarly journals β-elemene suppresses Warburg effect in NCI-H1650 non-small-cell lung cancer cells by regulating the miR-301a-3p/AMPKα axis

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Lin Li ◽  
Dongkai Zhao ◽  
Guangyu Cheng ◽  
Qingjie Li ◽  
Yunjie Chu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Warburg Effect ◽  
Glucose Transporter ◽  
A549 Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Glucose Transporter 1 ◽  
The Warburg Effect

Abstract β-elemene has been evidenced to suppress the development of numerous cancers including lung cancer. Previous research has found that in A549 cells, β-elemene increased the expression of adenosine monophosphate-activated protein kinase (AMPK) α (AMPKα), which negatively regulates the Warburg effect. Bioinformatics predicted that binding sites exist between AMPKα and miR-301a-3p, an miRNA that has shown oncogenic function in many cancers. The aim of this work was to investigate the effect of β-elemene on the Warburg effect in non-small-cell lung cancer (NSCLC) cells and its mechanism. Herein, the expression of miR-301a-3p was evaluated in NSCLC cells. Then, miR-301a-3p was overexpressed or silenced by mimics or inhibitors, respectively, followed by treatment with AMPK agonists or antagonists. NSCLC cells subjected to miR-301a-3p overexpression or inhibition were further treated with β-elemene. The results demonstrated that AMPKα was targeted and negatively regulated by miR-301a-3p. AMPKα agonists attenuated the Warburg effect in NSCLC cells induced by miR-301a-3p, as evidenced by the decrease in glucose level, lactic acid level, and expression of metabolism-related enzymes (glucose transporter 1 (GLUT1), hexokinase 1 (HK1), and lactate dehydrogenase A (LDHA)). Additionally, β-elemene suppressed the expression of miR-301a-3p, enhanced that of AMPKα, and inhibited the Warburg effect in NSCLC cells. The results indicated that β-elemene attenuates the Warburg effect in NSCLC cells, possibly by mediating the miR-301a-3p/AMPKα axis.

scholarly journals Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2743
Author(s):  
Caterina Miro ◽  
Annarita Nappi ◽  
Annunziata Gaetana Cicatiello ◽  
Emery Di Cicco ◽  
Serena Sagliocchi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Squamous Cell ◽  
Warburg Effect ◽  
Lactate Production ◽  
Metabolic Stress ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Glycolytic Flux ◽  
The Warburg Effect

Cancer angiogenesis is required to support energetic demand and metabolic stress, particularly during conditions of hypoxia. Coupled to neo-vasculogenesis, cancer cells rewire metabolic programs to sustain growth, survival and long-term maintenance. Thyroid hormone (TH) signaling regulates growth and differentiation in a variety of cell types and tissues, thus modulating hyper proliferative processes such as cancer. Herein, we report that TH coordinates a global program of metabolic reprogramming and induces angiogenesis through up-regulation of the VEGF-A gene, which results in the enhanced proliferation of tumor endothelial cells. In vivo conditional depletion of the TH activating enzyme in a mouse model of cutaneous squamous cell carcinoma (SCC) reduces the concentration of TH in the tumoral cells and results in impaired VEGF-A production and attenuated angiogenesis. In addition, we found that TH induces the expression of the glycolytic genes and fosters lactate production, which are key traits of the Warburg effect. Taken together, our results reveal a TH–VEGF-A–HIF1α regulatory axis leading to enhanced angiogenesis and glycolytic flux, which may represent a target for SCC therapy.

scholarly journals SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Xiao-bin Lv ◽  
Lijuan Liu ◽  
Chun Cheng ◽  
Bentong Yu ◽  
Longxin Xiong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Warburg Effect ◽  
The Warburg Effect

scholarly journals Tumor Suppressor SMAR1 Regulates PKM Alternative Splicing by HDAC6 Mediated Deacetylation of PTBP1

2021 ◽  
Author(s):  
Arpankumar Choksi ◽  
Apoorva Parulekar ◽  
Richa Pant ◽  
Vibhuti Kumar Shah ◽  
Ramakrishna Nimma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Alternative Splicing ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Breast Cancer Cell Lines ◽  
Alternative Splicing Events ◽  
Isoform Expression ◽  
The Warburg Effect

Abstract Background:Highly proliferating cancer cells exhibit the Warburg effect by regulation of PKM alternative splicing and promoting the expression of PKM2. Majority of the alternative splicing events are known to occur in the nuclear matrix where various MARBPs actively participate in the alternative splicing events. SMAR1, being a MARBP and an important tumor suppressor, is known to regulate the splicing of various cancer-associated genes. This study focuses on the regulation of PKM alternative splicing and inhibition of the Warburg effect by SMAR1.Methods:Immunohistochemistry was performed in breast cancer patient samples to establish the correlation between SMAR1 and PKM isoform expression. Further, expression of PKM isoforms upon modulation in SMAR1 expression in breast cancer cell lines was quantified by qRT-PCR and western blot. The acetylation status of PTBP1 was estimated by immunoprecipitation along with its enrichment on PKM pre-mRNA by CLIP in SMAR1 knockdown conditions. The role of SMAR1 in tumor metabolism and tumorigenesis was explored by in vitro enzymatic assays and functional assays upon SMAR1 knockdown. Besides, in vivo tumor formation by injecting adeno-SMAR1 transduced MDA-MB-231 cells in NOD/SCID mice was performed. Results:The expression profile of SMAR1 and PKM isoforms in breast cancer patients revealed that SMAR1 has an inverse correlation with PKM2 and a positive correlation with PKM1. Further quantitative PKM isoform expression upon modulation in SMAR1 expression also reflects that SMAR1 promotes the expression of PKM1 over tumorigenic isoform PKM2. SMAR1 deacetylates PTBP1 via recruitment of HDAC6 resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. SMAR1 inhibits the Warburg effect, tumorigenic potential of cancer cells and in vivo tumor generation in PKM2 dependent manner.Conclusions:SMAR1 regulates PKM alternative splicing by causing HDAC6 dependent deacetylation of PTBP1, resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. Additionally, SMAR1 suppresses glucose utilization and lactate production via repression of PKM2 expression. This suggests that tumor suppressor SMAR1 inhibits tumor cell metabolism and tumorigenic properties of cancer cells via regulation of PKM alternative splicing.

scholarly journals Berbamine Inhibits Cell Proliferation and Migration and Induces Cell Death of Lung Cancer Cells via Regulating c-Maf, PI3K/Akt, and MDM2-P53 Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Lili Liu ◽  
Zhiying Xu ◽  
Binbin Yu ◽  
Li Tao ◽  
Ying Cao
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Colony Formation ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Migration And Invasion ◽  
And Migration ◽  
Proliferation And Migration

Berbamine (BBM) is a natural product isolated from Berberis amurensis Rupr. We investigated the influence of BBM on the cell viability, proliferation, and migration of lung cancer cells and explored the possible mechanisms. The cell viability and proliferation of lung cancer cells were evaluated by MTT assay, EdU assay, and colony formation assay. Migration and invasion abilities of cancer cells were determined through wound scratch assay and Transwell assay. Cell death was evaluated by cell death staining assay and ELISA. The expressions of proteins were evaluated using western blot assay. A xenograft mouse model derived from non-small-cell lung cancer cells was used to detect the effect of BBM on tumor growth and metastasis in vivo. Both colony formation and EdU assays results revealed that BBM (10 μM) significantly inhibited the proliferation of A549 cells ( P < 0.001 ). BBM (10 μM) also significantly inhibited the migration and invasion ability of cancer cells in wound scratch and Transwell assays. Trypan blue assay and ELISA revealed that BBM (20 μM) significantly induced cell death of A549 cells. In xenograft mouse models, the tumor volume was significantly smaller in mice treated with BBM (20 mg/kg). The western blotting assay showed that BBM inhibited the PI3K/Akt and MDM2-p53 signaling pathways, and BBM downregulated the expression of c-Maf. Our results show that BBM inhibits proliferation and metastasis and induces cell death of lung cancer cells in vitro and in vivo. These effects may be achieved by BBM reducing the expression of c-Maf and regulating the PI3K/Akt and MDM2-p53 pathways.

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

2021 ◽  
Vol 21 ◽  
Author(s):  
Yiyan Song Yang ◽  
Songyisha Yang ◽  
Dejia Li ◽  
Wen Li
Keyword(s):  
Lung Cancer ◽  
Vitamin D ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Warburg Effect ◽  
Small Cell ◽  
Small Cell Lung ◽  
The Warburg Effect

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.

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