Obesity Promotes Aerobic Glycolysis in Prostate Cancer Cells

Abstract

Obesity is the leading preventable comorbidity associated with increased prostate cancer-related recurrence and mortality. Epidemiological and clinical studies indicate that a BMI >30 is associated with increased oxidative DNA damage within the prostate gland and increased prostate cancer-related mortality. Here we provide evidence that obesity promotes worse clinical outcome through induction of metabolic abnormalities known to promote genotoxic stress. We have previously reported that blood serum derived from obese mice may enhance the proliferative and invasive potential of human prostate cancer cell lines ex vivo. Here we show that a 1 hour exposure of LNCaP or PacMetUT1 prostate cancer cell lines and non-malignant RWPE-1 prostate epithelial cells to 2% serum from obese mice induces markers of aerobic glycolysis relative to those exposed to serum from non-obese mice. This metabolic change was correlated with accumulation of reactive oxygen species (ROS) and increased frequency of DNA double-strand breaks. Interestingly, N-tert-Butylhydroxylamine (NtBHA), an antioxidant, significantly suppressed markers of aerobic glycolysis in the cells exposed to Ob serum, suggesting that ROS contributes to a metabolic shift toward aerobic glycolysis. Here we describe obesity-induced changes in key metabolic markers that impact prostate cancer cell progression and explore the role of antioxidants in ameliorating these effects.

Transcriptome evaluation of the relation between body mass index and prostate cancer outcomes

“…We a priori selected and investigated 6 metabolic category pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG): glycolysis and gluconeogenesis; citrate cycle; D‐glutamine and D‐glutamate metabolism; valine, leucine, and isoleucine degradation; methane metabolism; and glycine, serine, and threonine metabolism (Table ). These pathways were selected because of the potential influence of obesity and metabolic derangement on their gene expression . KLK3 expression was also assessed according to the BMI category because low androgen receptor levels are associated with obesity …”

“…These pathways were selected because of the potential influence of obesity and metabolic derangement on their gene expression. [24][25][26] KLK3 expression was also assessed according to the BMI category because low androgen receptor levels are associated with obesity. 27…”

Translating Mechanism-Based Strategies to Break the Obesity−Cancer Link: A Narrative Review

“…Moreover, glycolysis has been shown to be enhanced in cancer cells in the context of obesity. 20,21 In addition, obesity is often associated with metabolic syndrome and diabetes, 22,23 conditions characterized by hyperglycemia and/or hypertriglyceridemia, 24 providing ample circulating nutrients to a developing tumor, even between feeding periods. 25 Both elevated serum glucose and triglyceride 26,27 levels have been associated with increased cancer risk.…”

Obesity: The Fat Tissue Disease Version of Cancer

“…This has built a growing body of consensus about the association of these two pathologies, besides their broadly proven correlation, given the numerous epidemiological and clinical studies pointing out the significantly higher relative risk to develop cancer in obese versus non-obese populations [ 47 , 48 ]. Explorations about these connecting bridges have yielded promising answers, such as the recognition of fat mass and obesity-associated genes (e.g., FTO ) as a common mechanistic basis for both cancer and obesity and the finding that obesity-associated dysmetabolism causes genotoxic stress in favor of cancer comorbidity [ 49 , 50 , 51 ]. This evidence adds to the results from many other in vitro [ 51 , 52 , 53 ], ex vivo [ 54 , 55 ], and in vivo studies [ 56 , 57 , 58 , 59 ] and has been reviewed and acknowledged by the International Agency for Research on Cancer, who announced that there is enough confident and unbiased evidence about the association of excess body weight with a reinforced cancer predisposition—in particular with regard to more than twelve types of cancer in various tissues/organ systems, such as blood, central nervous system, endometrium, esophagus, kidney, pancreas, liver, colon, postmenopausal breast, ovary, gallbladder, and thyroid gland—in agreement with the World Cancer Research Fund/American Institute for Cancer Research [ 58 , 60 ].…”