Abstract
There are an increasing number of reports on obesity being a key risk factor for the development of colon cancer. Our goal in this study was to explore the metabolic networks and molecular signaling pathways linking obesity, adipose tissue and colon cancer. Using in-vivo experiments, we found that mice fed a high-fat diet (HFD) and injected with MC38 colon cancer cells develop significantly larger tumors than their counterparts fed a control diet. In ex-vivo experiments, MC38 and CT26 colon cancer cells exposed to conditioned media (CM) from the adipose tissue of HFD-fed mice demonstrated significantly lower oxygen consumption rate as well as lower maximal oxygen consumption rate after carbonyl cyanide-4-trifluoromethoxy-phenylhydrazone treatment. In addition, in-vitro assays showed downregulated expression of mitochondrial genes in colon cancer cells exposed to CM prepared from the visceral fat of HFD-fed mice or to leptin. Interestingly, leptin levels detected in the media of adipose tissue explants co-cultured with MC38 cancer cells were higher than in adipose tissue explants cultures, indicating cross talk between the adipose tissue and the cancer cells. Salient findings of the present study demonstrate that this crosstalk is mediated at least partially by the JNK/STAT3-signaling pathway.
Highlights
Obesity caused by overnutrition and a sedentary life style leads to abnormal or excessive fat accumulation on the adipose tissue, induction of metabolic disorders and impaired health [1]
We show that products secreted from conditioned media (CM) prepared from mouse visceral adipose tissue (VAT) promote mitochondrial dysfunction of cancer cells, and that this effect is mediated by the c-Jun N-terminal kinase (JNK)/STAT-3-signaling pathway
Since leptin is directly correlated with obesity [23] and cancer progression [14], and activates the JNK/ STAT3-signaling pathway, we investigated whether leptin and the respective JNK/STAT3-signaling pathway [13, 24, 25] play some role in modulating the expression of mitochondrial or glycolytic genes
Summary
Obesity caused by overnutrition and a sedentary life style leads to abnormal or excessive fat accumulation on the adipose tissue, induction of metabolic disorders and impaired health [1]. Studies aimed at elucidating alterations in the mechanisms associated with obesity have found that mitochondrial dysfunction accompanies excess lipid accumulation and oxidative stress in several organs, such as the skeletal muscle and liver [2]. High insulin levels and insulin resistance have been shown to be directly associated with the suppressed mitochondrial function [3]. Mitochondrial suppression and dysfunction characterize cancer cells as they use aerobic glycolysis and glycolytic intermediates to generate energy and enhance growth, a phenomenon called “the Warburg effect”. Cancer cells generate important cofactors and redox components, such as high levels of reduced forms of NAD+, NADH, and NADPH. Altered metabolic activities like these can be linked to both mitochondrial oxidative phosphorylation (OXPHOS) and biogenesis inhibition, which can support a metastatic phenotype [4, 5]
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