Upregulation of glycolysis and oxidative phosphorylation in benzo[β]pyrene and arsenic-induced rat lung epithelial transformed cells

Abstract

Arsenic and benzo[β]pyrene (B[a]P) are common contaminants in developing countries. Many studies have investigated the consequences of arsenic and/or B[a]P-induced cellular transformation, including altered metabolism. In the present study, we show that, in addition to elevated glycolysis, B[a]P/arsenic-induced transformation also stimulates oxidative phosphorylation (OXPHOS). Proteomic data and immunoblot studies demonstrated that enzymatic activities, involved in both glycolysis and OXPHOS, are upregulated in the primary transformed rat lung epithelial cell (TLEC) culture, as well as in subcloned TLEC cell lines (TMCs), indicating that OXPHOS was active and still contributed to energy production. LEC expression, of the glycolytic enzyme phosphoglycerate mutase (PGAM) and the TCA cycle enzyme alpha-ketoglutarate dehydrogenase (OGDH), revealed an alternating cyclic pattern of glycolysis and OXPHOS during cell transformation. We also found that the expression levels of hypoxia-inducible factor-1β were consistent with the pattern of glycolysis during the course of transformation. Low doses of an ATP synthase inhibitor depleted endogenous ATP levels to a greater extent in TLECs, compared to parental LECs, indicating greater sensitivity of B[a]P/arsenic-transformed cells to ATP depletion. However, TLEC cells exhibited better survival under hypoxia, possibly due to further induction of anaerobic glycolysis. Collectively, our data indicate that B[a]P/arsenic-transformed cells can maintain energy production through upregulation of both glycolysis and OXPHOS. Selective inhibition of metabolic pathways may serve as a therapeutic option for cancer therapy.

Environmental carcinogenesis and pH homeostasis: Not only a matter of dysregulated metabolism

“…More recently, a Warburg effect has also been evidenced in arsenic-treated non-malignant pulmonary epithelial cell line BEAS-2B [223]. Furthermore, an upregulation of cell energy metabolism in B[a]P/arsenic-transformed lung epithelial cells has been reported [224]. Thus, it would be worth testing the role of NHE1 in the carcinogenic effects of arsenic as well as many other carcinogenic compounds, notably when present in chemical mixtures.…”

Subchronic arsenism-induced oxidative stress and inflammation contribute to apoptosis through mitochondrial and death receptor dependent pathways in chicken immune organs

“…For another in rats, As 2 O 3 at a level of 5 mg/kg body weight (BW)/day elevated the levels of caspase-3 and nitric oxide and increased the expression of nucleic factor κB (NF-κB) p65 in the liver [ 6 ], which indicated the symptom of intoxication. Moreover, it has been also proved that longtime exposure to arsenic is deleterious to the liver [ 7 ], lung epithelial transformed cells [ 8 ], skin [ 9 ] and arsenic alters multiple cellular pathways, which include expression of cytokines, promotion and resistance of apoptosis and increasing oxidative stress [ 10 ], these alterations lead to disease manifestations. Recently, our studies have shown that subchronic exposure to As 2 O 3 in excess of 0.625 mg/kg BW causes inflammation, oxidative stress and heat shock response in the liver [ 11 ], brain [ 12 ] and immune organs [ 13 ].…”

Linking Metabolic Reprogramming, Plasticity and Tumor Progression

“…On the contrary, downregulation of glycolysis [ 23 ] or induction of mitochondria biogenesis [ 24 ] lead to the restoration of OXPHOS and subsequent death of malignant cells. Despite this common view, there are experimental data suggesting that high levels of OXPHOS are important to many cancer cells models and tumors [ 25 , 26 ].…”