Bisphenol A Alters the Energy Metabolism of Stromal Cells and Could Promote Bladder Cancer Progression

Abstract

Bisphenol A (BPA) is an endocrine-disrupting molecule used in plastics. Through its release in food and the environment, BPA can be found in humans and is mostly excreted in urine. The bladder is therefore continuously exposed to this compound. BPA can bind to multiple cell receptors involved in proliferation, migration and invasion pathways, and exposure to BPA is associated with cancer progression. Considering the physiological concentrations of BPA in urine, we tested the effect of nanomolar concentrations of BPA on the metabolism of bladder fibroblasts and cancer-associated fibroblasts (CAFs). Our results show that BPA led to a decreased metabolism in fibroblasts, which could alter the extracellular matrix. Furthermore, CAF induction triggered a metabolic switch, similar to the Warburg effect described in cancer cells. Additionally, we demonstrated that nanomolar concentrations of BPA could exacerbate this metabolic switch observed in CAFs via an increased glycolytic metabolism, leading to greater acidification of the extracellular environment. These findings suggest that chronic exposure to BPA could promote cancer progression through an alteration of the metabolism of stromal cells.

Evaluation of a Serum-Free Medium for Human Epithelial and Stromal Cell Culture

“…Indeed, mitochondrial dysfunction is often associated with known pathologies [ 31 , 32 , 33 ]. For example, Pellerin et al showed that cancer-associated fibroblasts (CAFs) exhibit modified metabolism, with increased basal and maximal glycolysis (ECAR) compared to normal fibroblasts [ 34 ] (also reviewed in [ 35 , 36 , 37 ]). The results obtained in the current study indicated that the ATP production through mitochondrial respiration and mitochondrial capacity tended to be greater in the cell culture conditions using SFM compared to FBSCM.…”

Bisphenols A and S Alter the Bioenergetics and Behaviours of Normal Urothelial and Bladder Cancer Cells

“…Mito Stress media consisted of XF Base Medium supplemented with 2 mM L-glutamine, 1 mM sodium pyruvate (Wisent Bioproducts Inc.) and 10 mM D-(+)-glucose (Millipore Sigma). The extracellular acidification rate (ECAR), representative of glycolytic metabolism, and the oxygen consumption rate (OCR), representative of mitochondrial respiration, were determined using the XFe Extracellular Flux Analyzer (Agilent/Seahorse Bioscience) [ 20 , 25 ].…”

“…It was previously demonstrated that the energy metabolism of healthy bladder fibroblasts decreased after chronic exposure to physiological concentrations of BPA. In contrast, BPA-exposed cancer-associated fibroblasts (CAFs) displayed an increased glycolytic metabolism, leading to extracellular acidification [ 20 ]. This enhanced acidification can lead to the inhibition of immune cells, such as monocytes, as well as reorganization of the extracellular matrix [ 21 , 22 ], thus potentially promoting bladder cancer progression [ 20 ].…”

“…In contrast, BPA-exposed cancer-associated fibroblasts (CAFs) displayed an increased glycolytic metabolism, leading to extracellular acidification [ 20 ]. This enhanced acidification can lead to the inhibition of immune cells, such as monocytes, as well as reorganization of the extracellular matrix [ 21 , 22 ], thus potentially promoting bladder cancer progression [ 20 ]. The hypothesis of this study was that BPA and BPS would impact the energy metabolism and properties of normal urothelial cells and bladder cancer cells, i.e., migration, proliferation and expression of cell markers of invasive potential, which could promote bladder cancer initiation and progression.…”

Glucuronidated Metabolites of Bisphenols A and S Alter the Properties of Normal Urothelial and Bladder Cancer Cells

“…Mito Stress media contained XF Base Medium supplemented with 2 mM L-glutamine, 1 mM sodium pyruvate (Wisent Bioproducts Inc.) and 10 mM D-(+)-glucose (Millipore Sigma, Oakville, ON, Canada). The extracellular acidification rate (ECAR), representative of the glycolytic capacity, and the oxygen consumption rate (OCR), representative of the mitochondrial respiration, were determined using the XFe Extracellular Flux Analyzer (Agilent/Seahorse Bioscience) [ 34 , 35 ].…”