Role of TNFα and leptin signaling in colon cancer incidence and tumor growth under obese phenotype

Singh, Shweta; Mayengbam, Shyamananda Singh; Chouhan, Surbhi; Deshmukh, Bhavana; Ramteke, Pranay; Athavale, Dipti; Bhat, Manoj Kumar

doi:10.1016/j.bbadis.2019.165660

Cited by 17 publications

(6 citation statements)

References 48 publications

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“…Studies from our group and others have demonstrated the role of obesity in supporting rapid cancer progression. Earlier we reported that in AOM/DSS chemical carcinogen model the incidence of cancerous polyp formation was higher in diet-induced obese mice [ 8 ]. To evaluate specifically the role of cholesterol in colon cancer initiation and progression; AOM/DSS-mediated polyps’ formation, as well as MC-38 isograft-induced tumor progression models, were used.…”

Section: Resultsmentioning

confidence: 99%

“…1.5 to 2.0 in men, 1.2 to 1.5 in women [ 4 , 5 ], and worsen the prognosis of cancer patients [ 6 ]. Earlier findings from our group have demonstrated the effect of obesity on promoting colon cancer initiation, and melanoma tumor progression in mouse models [ 7 , 8 ]. However, concrete evidence through which hypercholesterolemia influences the risk of cancer, and tumorigenesis is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells

Mayengbam,

Singh,

Yaduvanshi

et al. 2023

Cancer Metab

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Hypercholesterolemia is often correlated with obesity which is considered a risk factor for various cancers. With the growing population of hypercholesterolemic individuals, there is a need to understand the role of increased circulatory cholesterol or dietary cholesterol intake towards cancer etiology and pathology. Recently, abnormality in the blood cholesterol level of colon cancer patients has been reported. In the present study, we demonstrate that alteration in cholesterol levels (through a high-cholesterol or high-fat diet) increases the incidence of chemical carcinogen-induced colon polyp occurrence and tumor progression in mice. At the cellular level, low-density lipoprotein cholesterol (LDLc) and high-density lipoprotein cholesterol (HDLc) promote colon cancer cell proliferation by tuning the cellular glucose and lipid metabolism. Mechanistically, supplementation of LDLc or HDLc promotes cellular glucose uptake, and utilization, thereby, causing an increase in lactate production by colon cancer cells. Moreover, LDLc or HDLc upregulates aerobic glycolysis, causing an increase in total ATP production through glycolysis, and a decrease in ATP generation by OXPHOS. Interestingly, the shift in the metabolic status towards a more glycolytic phenotype upon the availability of cholesterol supports rapid cell proliferation. Additionally, an alteration in the expression of the molecules involved in cholesterol uptake along with the increase in lipid and cholesterol accumulation was observed in cells supplemented with LDLc or HDLc. These results indicate that colon cancer cells directly utilize the cholesterol associated with LDLc or HDLc. Moreover, targeting glucose metabolism through LDH inhibitor (oxamate) drastically abrogates the cellular proliferation induced by LDLc or HDLc. Collectively, we illustrate the vital role of cholesterol in regulating the cellular glucose and lipid metabolism of cancer cells and its direct effect on the colon tumorigenesis. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells

Mayengbam,

Singh,

Yaduvanshi

et al. 2023

Cancer Metab

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“…The fact that p53 is activated in the adipose tissue of obese animals, along with the results here presented concerning a putative direct role of p53 in controlling Upd2/ Leptin expression, demonstrates the importance of p53 in regulating metabolism. This is particularly interesting given that epidemiological studies over the last few decades have shown a strong influence of obesity on cancer risk and that increased Leptin can have hormone-like functions affecting tumor development (Andò et Singh et al, 2020;Xu et al, 2020). In this context, our results give insights toward the molecular understanding of p53 activation under metabolic stress and its possible role in tumor suppression acting at either local or organismal level.…”

Section: P53-dependent Leptin Regulation In Animal Physiology and Dismentioning

confidence: 71%

Fat Body p53 Regulates Systemic Insulin Signaling and Autophagy under Nutrient Stress via Drosophila Upd2 Repression

et al. 2020

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“…The fact that p53 is activated in the adipose tissue of obese animals, along with the results here presented concerning a putative direct role of p53 in controlling Upd2/ Leptin expression, demonstrates the importance of p53 in regulating metabolism. This is particularly interesting given that epidemiological studies over the last few decades have shown a strong influence of obesity on cancer risk and that increased Leptin can have hormone-like functions affecting tumor development (Ando `et al, 2019;Maroni, Cell Reports 33, 108321, October 27, 2020 11 Article ll OPEN ACCESS 2020;Singh et al, 2020;Xu et al, 2020). In this context, our results give insights toward the molecular understanding of p53 activation under metabolic stress and its possible role in tumor suppression acting at either local or organismal level.…”

Section: P53-dependent Leptin Regulation In Animal Physiology and Diseasementioning

confidence: 99%

Fat Body p53 Regulates Systemic Insulin Signaling and Autophagy Under Nutrient Stress via <i>Drosophila</i> Upd2 Repression

et al. 2020

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The tumor suppressor p53 regulates multiple metabolic pathways at the cellular level. However, its role in the context of a whole animal response to metabolic stress is poorly understood. Using Drosophila, we show that AMP-activated protein kinase (AMPK)-dependent Dmp53 activation is critical for sensing nutrient stress, maintaining metabolic homeostasis, and extending organismal survival. Under both nutrient deprivation and high-sugar diet, Dmp53 activation in the fat body represses expression of the Drosophila Leptin analog, Unpaired-2 (Upd2), which remotely controls Dilp2 secretion in insulin-producing cells. In starved Dmp53depleted animals, elevated Upd2 expression in adipose cells and activation of Upd2 receptor Domeless in the brain result in sustained Dilp2 circulating levels and impaired autophagy induction at a systemic level, thereby reducing nutrient stress survival. These findings demonstrate an essential role for the AMPK-Dmp53 axis in nutrient stress responses and expand the concept that adipose tissue acts as a sensing organ that orchestrates systemic adaptation to nutrient status.

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Role of TNFα and leptin signaling in colon cancer incidence and tumor growth under obese phenotype

Cited by 17 publications

References 48 publications

Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells

Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells

Fat Body p53 Regulates Systemic Insulin Signaling and Autophagy under Nutrient Stress via Drosophila Upd2 Repression

Fat Body p53 Regulates Systemic Insulin Signaling and Autophagy Under Nutrient Stress via <i>Drosophila</i> Upd2 Repression

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