Energy balance-related factors and risk of colorectal cancer expressing different levels of proteins involved in 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.

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

The Journal of Pathology Clinical Research ◽

10.1002/cjp2.250 ◽

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

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

International Journal of Molecular Sciences ◽

10.3390/ijms19092752 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2752 ◽

Cited By ~ 9

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.

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

Cancer Medicine ◽

10.1002/cam4.521 ◽

2015 ◽

Vol 4 (11) ◽

pp. 1730-1741 ◽

Cited By ~ 13

Author(s):

Yanglei Jia ◽

Zengyi Ma ◽

Xiaofei Liu ◽

Wenjing Zhou ◽

Shan He ◽

...

Keyword(s):

Colorectal Cancer ◽

Warburg Effect ◽

Diabetic Rats ◽

The Warburg Effect

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Worenine reverses the Warburg effect and inhibits colon cancer cell growth by negatively regulating HIF-1α

Cellular & Molecular Biology Letters ◽

10.1186/s11658-021-00263-y ◽

2021 ◽

Vol 26 (1) ◽

Author(s):

Lijiang Ji ◽

Weixing Shen ◽

Feng Zhang ◽

Jie Qian ◽

Jie Jiang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Cell Growth ◽

Cancer Cell ◽

Warburg Effect ◽

Lactate Production ◽

Colorectal Cancer Cell ◽

Cell Cycle Distribution ◽

Cancer Cell Growth ◽

The Warburg Effect

Abstract Background Some natural compounds inhibit cancer cell growth in various cancer cell lines with fewer side effects than traditional chemotherapy. Here, we explore the pharmacological effects and mechanisms of worenine (isolated from Coptis chinensis) against colorectal cancer. Methods The effects of worenine on colorectal cancer cell proliferation, colony formation and cell cycle distribution were measured. Glycolysis was investigated by examining glucose uptake and consumption, lactate production, and the activities and expressions of glycolysis enzymes (PFK-L, HK2 and PKM2). HIF-1α was knocked down and stimulated in vitro to investigate the underlying mechanisms. Results Worenine somewhat altered the glucose metabolism and glycolysis (Warburg effect) of cancer cells. Its anti-cancer effects and capability to reverse the Warburg effect were similar to those of HIF-1α siRNA and weakened by deferoxamine (an HIF-1α agonist). Conclusion It is suggested that worenine targets HIF-1α to inhibit colorectal cancer cell growth, proliferation, cell cycle progression and the Warburg effect.

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Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

Frontiers in Oncology ◽

10.3389/fonc.2021.796839 ◽

2021 ◽

Vol 11 ◽

Author(s):

Juan Liu ◽

Chao Yang ◽

Xiao-Mei Huang ◽

Pan-Pan Lv ◽

Ya-Kun Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Warburg Effect ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cells ◽

Targeted Agents ◽

Related Factors ◽

Mesenchymal Transition ◽

Molecular Targeted Agents ◽

Hcc Cells ◽

The Warburg Effect

The transcription suppressor factor FBI-1 (the factor that binds to inducer of short transcripts-1) is an important regulator of hepatocellular carcinoma (HCC). In this work, the results showed that FBI-1 promoted the Warburg effect and enhances the resistance of hepatocellular carcinoma cells to molecular targeted agents. Knockdown of FBI-1 via its small-interfering RNA (siRNA) inhibited the ATP level, lactate productions, glucose uptake or lactate dehydrogenase (LDH) activation of HCC cells. Transfection of siFBI-1 also decreased the expression of the Warburg-effect-related factors: hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A (LDHA), or GLUT1, and the epithelial–mesenchymal transition-related factors, Vimentin or N-cadherin. The positive correlation between the expression of FBI-1 with HIF-1α, LDHA, or GLUT1 was confirmed in HCC tissues. Mechanistically, the miR-30c repressed the expression of HIF-1α by binding to the 3′-untranslated region (3′-UTR) of HIF-1α in a sequence-specific manner, and FBI-1 enhanced the expression of HIF-1α and HIF-1α pathway’s activation by repressing the expression of miR. By modulating the miR-30c/HIF-1α, FBI-1 promoted the Warburg effect or the epithelial–mesenchymal transition of HCC cells and promoted the resistance of HCC cells to molecular targeted agents.

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Polymorphisms in the mTOR-PI3K-Akt pathway, energy balance-related exposures and colorectal cancer risk in the Netherlands Cohort Study

BioData Mining ◽

10.1186/s13040-021-00286-3 ◽

2022 ◽

Vol 15 (1) ◽

Author(s):

Colinda C.J.M. Simons ◽

Leo J. Schouten ◽

Roger W.L. Godschalk ◽

Frederik-Jan van Schooten ◽

Monika Stoll ◽

...

Keyword(s):

Physical Activity ◽

Colorectal Cancer ◽

Colon Cancer ◽

Cohort Study ◽

Energy Balance ◽

Risk Scores ◽

Akt Pathway ◽

Related Factors ◽

Men And Women ◽

Polygenic Risk

Abstract Background The mTOR-PI3K-Akt pathway influences cell metabolism and (malignant) cell growth. We generated sex-specific polygenic risk scores capturing natural variation in 7 out of 10 top-ranked genes in this pathway. We studied the scores directly and in interaction with energy balance-related factors (body mass index (BMI), trouser/skirt size, height, physical activity, and early life energy restriction) in relation to colorectal cancer (CRC) risk in the Netherlands Cohort Study (NLCS) (n=120,852). The NLCS has a case-cohort design and 20.3 years of follow-up. Participants completed a baseline questionnaire on diet and cancer in 1986 when 55–69 years old. ~75% of the cohort returned toenail clippings used for DNA isolation and genotyping (n subcohort=3,793, n cases=3,464). To generate the scores, the dataset was split in two and risk alleles were defined and weighted based on sex-specific associations with CRC risk in the other dataset half, because there were no SNPs in the top-ranked genes associated with CRC risk in previous genome-wide association studies at a significance level p<1*10−5. Results Cox regression analyses showed positive associations between the sex-specific polygenic risk scores and colon but not rectal cancer risk in men and women, with hazard ratios for continuously modeled scores close to 1.10. There was no modifying effect observed of the scores on associations between the energy balance-related factors and CRC risk. However, BMI (in men), non-occupational physical activity (in women), and height (in men and women) were associated with the risk of CRC, in particular (proximal and distal) colon cancer, in the direction as expected in the lower tertiles of the sex-specific polygenic risk scores. Conclusions Current data suggest that the mTOR-PI3K-Akt pathway may be involved in colon cancer development. This study thereby sheds more light on colon cancer etiology through use of genetic variation in the mTOR-PI3K-Akt pathway.

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