scholarly journals N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: implication in colorectal cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Senxu Lu ◽  
Li Han ◽  
Xiaoyun Hu ◽  
Tong Sun ◽  
Dongping Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Warburg Effect ◽  
Molecular Mechanisms ◽  
Atp Hydrolysis ◽  
Rna Stability ◽  
Functional Domain ◽  
Dependent Manner ◽  
Glycolytic Metabolism ◽  
Mitochondrial Energy Metabolism ◽  
The Warburg Effect

Abstract Background Accumulating evidence shows that N6-methyladenine (m6A) modulators contribute to the etiology and progression of colorectal cancer (CRC). However, the exact mechanisms of m6A reader involved in glycolytic metabolism remain vague. This article aimed to crosstalk the m6A reader with glycolytic metabolism and reveal a new mechanism for the progression of CRC. Methods The relationship between candidate lncRNA and m6A reader was analyzed by bioinformatics, ISH and IHC assays. In vivo and in vitro studies (including MTT, CFA, trans-well, apoptosis, western blot, qRT-PCR and xenograft mouse models) were utilized to explore the biological functions of these indicators. Lactate detection, ATP activity detection and ECAR assays were used to verify the biological function of the downstream target. The bioinformatics, RNA stability, RIP experiments and RNA pull-down assays were used to explore the potential molecular mechanisms. Results We identified that the crosstalk of the m6A reader IMP2 with long-noncoding RNA (lncRNA) ZFAS1 in an m6A modulation-dependent manner, subsequently augmented the recruitment of Obg-like ATPase 1 (OLA1) and adenosine triphosphate (ATP) hydrolysis and glycolysis during CRC proliferation and progression. Specifically, IMP2 and ZFAS1 are significantly overexpressed with elevated m6A levels in CRC cells and paired CRC cohorts (n = 144). These indicators could be independent biomarkers for CRC prognostic prediction. Notably, IMP2 regulated ZFAS1 expression and enhanced CRC cell proliferation, colony formation, and apoptosis inhibition; thus, it was oncogenic. Mechanistically, ZFAS1 is modified at adenosine +843 within the RGGAC/RRACH element in an m6A-dependent manner. Thus, direct interaction between the KH3–4 domain of IMP2 and ZFAS1 where IMP2 serves as a reader for m6A-modified ZFAS1 and promotes the RNA stability of ZFAS1 is critical for CRC development. More importantly, stabilized ZFAS1 recognizes the OBG-type functional domain of OLA1, which facilitated the exposure of ATP-binding sites (NVGKST, 32–37), enhanced its protein activity, and ultimately accelerated ATP hydrolysis and the Warburg effect. Conclusions Our findings reveal a new cancer-promoting mechanism, that is, the critical modulation network underlying m6A readers stabilizes lncRNAs, and they jointly promote mitochondrial energy metabolism in the pathogenesis of CRC.

The Warburg effect promoted the activation of the NLRP3 inflammasome induced by Ni-refining fumes in BEAS-2B cells

2020 ◽  
Vol 36 (8) ◽  
pp. 580-590
Author(s):  
Rui Wang ◽  
Sheng-Yuan Wang ◽  
Yue Wang ◽  
Rui Xin ◽  
Bing Xia ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Warburg Effect ◽  
Hypoxia Inducible Factor ◽  
Lactate Production ◽  
Control Group ◽  
Dependent Manner ◽  
Chain Reactions ◽  
Protein Levels ◽  
Polymerase Chain Reactions ◽  
The Warburg Effect

Nickel (Ni) is a known human carcinogen that has an adverse effect on various human organs in occupational workers during Ni refinement and smelting. In the present study, we used real-time polymerase chain reactions, Western blot analysis, and a lactate production assay to investigate whether an increase in the NLRP3 inflammasome induced by Ni-refining fumes was associated with the Warburg effect in BEAS-2B cells, a nonmalignant pulmonary epithelial line. Exposure to Ni-refining fumes suppressed cell proliferation and increased lactate production compared with those in an untreated control group in a dose- and time-dependent manner. Ni-refining fumes induced the Warburg effect, which was observed based on increases in the levels of hypoxia-inducible factor-1α, hexokinase 2, pyruvate kinase isozyme type M2, and lactate dehydrogenase A. In addition, Ni-refining fumes promoted increased expression of NLRP3 at both the gene and protein levels. Furthermore, inhibition of the Warburg effect by 2-Deoxy-d-glucose reversed the increased expression of NLRP3 induced by Ni-refining fumes. Collectively, our data demonstrated that the Warburg effect can promote the expression of the NLRP3 inflammasome induced by the Ni-refining fumes in BEAS-2B cells. This indicates a new phenomenon in which alterations in energy production in human cells induced by Ni-refining fumes regulate the inflammatory response.

scholarly journals Promotion of the Warburg effect is associated with poor benefit from adjuvant chemotherapy in colorectal cancer

2020 ◽  
Vol 111 (2) ◽  
pp. 658-666
Author(s):  
Masashi Kitazawa ◽  
Tomohisa Hatta ◽  
Yusuke Sasaki ◽  
Kazuhiko Fukui ◽  
Koji Ogawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Warburg Effect ◽  
The Warburg Effect

scholarly journals The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Chang Liu ◽  
Ying Jin ◽  
Zhimin Fan
Keyword(s):  
Overall Survival ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Cancer Patients ◽  
Warburg Effect ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Glycolysis Process ◽  
New Molecular Targets ◽  
The Warburg Effect

Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to the diversity, heterogeneity, and adaptability to environmental alters in clinic. To determine more possibilities for cancer therapy, recent studies have begun to explore changes in the metabolism, especially glycolysis. The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. However, the association between glycolysis and chemoresistance and molecular mechanisms of glycolysis-induced chemoresistance remains unclear. This review describes the mechanism of glycolysis-induced chemoresistance from the aspects of glycolysis process, signaling pathways, tumor microenvironment, and their interactions. The understanding of how glycolysis induces chemoresistance may provide new molecular targets and concepts for cancer therapy.

scholarly journals The inverse association of cancer and Alzheimer's: a bioenergetic mechanism

2013 ◽  
Vol 10 (82) ◽  
pp. 20130006 ◽  
Author(s):  
Lloyd A. Demetrius ◽  
David K. Simon
Keyword(s):  
Warburg Effect ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Inverse Association ◽  
Inverse Relation ◽  
Bioenergetic Model ◽  
Metabolic Alteration ◽  
Metabolic Dysregulation ◽  
Age Related ◽  
The Warburg Effect

The sporadic forms of cancer and Alzheimer's disease (AD) are both age-related metabolic disorders. However, the molecular mechanisms underlying the two diseases are distinct: cancer is described by essentially limitless replicative potential, whereas neuronal death is a key feature of AD. Studies of the origin of both diseases indicate that their sporadic forms are the result of metabolic dysregulation, and a compensatory increase in energy transduction that is inversely related. In cancer, the compensatory metabolic effect is the upregulation of glycolysis—the Warburg effect; in AD, a bioenergetic model based on the interaction between astrocytes and neurons indicates that the compensatory metabolic alteration is the upregulation of oxidative phosphorylation—an inverse Warburg effect. These two modes of metabolic alteration could contribute to an inverse relation between the incidence of the two diseases. We invoke this bioenergetic mechanism to furnish a molecular basis for an epidemiological observation, namely the incidence of sporadic forms of cancer and AD is inversely related. We furthermore exploit the molecular mechanisms underlying the diseases to propose common therapeutic strategies for cancer and AD based on metabolic intervention.

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 Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

2021 ◽  
Vol 22 (12) ◽  
pp. 6434
Author(s):  
Aldona Kasprzak
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Glucose Metabolism ◽  
Warburg Effect ◽  
Mapk Signaling ◽  
Colorectal Carcinogenesis ◽  
Insulin Like Growth Factor ◽  
Aberrant Expression ◽  
The Warburg Effect

Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.

scholarly journals Expression of proteins associated with the Warburg‐effect and survival in colorectal cancer

2021 ◽  
Author(s):  
Kelly Offermans ◽  
Josien CA Jenniskens ◽  
Colinda CJM Simons ◽  
Iryna Samarska ◽  
Gregorio E Fazzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Warburg Effect ◽  
The Warburg Effect

scholarly journals Ascorbic Acid in Colon Cancer: From the Basic to the Clinical Applications

2018 ◽  
Vol 19 (9) ◽  
pp. 2752 ◽  
Author(s):  
Ibrahim El Halabi ◽  
Rachelle Bejjany ◽  
Rihab Nasr ◽  
Deborah Mukherji ◽  
Sally Temraz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Ascorbic Acid ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Tumour Regression ◽  
Therapeutic Concept ◽  
Therapeutic Benefits ◽  
Potential Benefits ◽  
The Warburg Effect

Given the safety and potential benefits of intravenous ascorbic acid (AA) administration in cancer patients, there is merit in further exploring this therapeutic concept. In this review, we discuss the potential benefits of intravenous AA administration on colorectal cancer and we specifically focus on its effect on glycolysis in mutant and wild type RAS. We perform a PubMed and Ovid MEDLINE search using ascorbic acid, intravenous vitamin C, KRAS mutation, BRAF mutation and colorectal cancer (CRC) as keywords. At the cellular level, colorectal cancer cells undergo a metabolic shift called the Warburg effect to allow for more glucose absorption and utilization of glycolysis. This shift also allows AA to enter which leads to a disruption in the Warburg effect and a shutdown of the downstream KRAS pathway in mutated KRAS colon cancer cells. At the clinical level, AA is associated with tumour regression in advanced disease and improved tolerability and side effects of standard therapy. Based on these findings, we conclude that further clinical trials are needed on a larger scale to examine the therapeutic benefits of AA in colon cancer.

scholarly journals Metformin prevents DMH ‐induced colorectal cancer in diabetic rats by reversing the warburg effect

2015 ◽  
Vol 4 (11) ◽  
pp. 1730-1741 ◽  
Author(s):  
Yanglei Jia ◽  
Zengyi Ma ◽  
Xiaofei Liu ◽  
Wenjing Zhou ◽  
Shan He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Warburg Effect ◽  
Diabetic Rats ◽  
The Warburg Effect

scholarly journals Peroxidan Plays a Tumor-Promoting Role in Oral Squamous Cell Carcinoma

2020 ◽  
Vol 21 (15) ◽  
pp. 5416 ◽  
Author(s):  
Miyako Kurihara-Shimomura ◽  
Tomonori Sasahira ◽  
Hiroyuki Shimomura ◽  
Tadaaki Kirita
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Warburg Effect ◽  
Molecular Mechanisms ◽  
Immunohistochemical Analysis ◽  
Heme Oxygenase 1 ◽  
Atp Production ◽  
The Warburg Effect

Despite dramatic progress in cancer diagnosis and treatment, the five-year survival rate of oral squamous cell carcinoma (OSCC) is still only about 50%. Thus, the need for elucidating the molecular mechanisms underlying OSCC is urgent. We previously identified the peroxidasin gene (PXDN) as one of several novel genes associated with OSCC. Although the PXDN protein is known to act as a tumor-promoting factor associated with the Warburg effect, its function and role in OSCC are poorly understood. In this study, we investigated the expression, function, and relationship with the Warburg effect of PXDN in OSCC. In immunohistochemical analysis of OSCC specimens, we observed that elevated PXDN expression correlated with lymph node metastasis and a diffuse invasion pattern. High PXDN expression was confirmed as an independent predictor of poor prognosis by multivariate analysis. The PXDN expression level correlated positively with that of pyruvate kinase (PKM2) and heme oxygenase-1 (HMOX1) and with lactate and ATP production. No relationship between PXDN expression and mitochondrial activation was observed, and PXDN expression correlated inversely with reactive oxygen species (ROS) production. These results suggest that PXDN might be a tumor progression factor causing a Warburg-like effect in OSCC.

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