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

Abstract

// Huachen Chen 1, * , Lai-Sheung Lee 2, * , Guanwu Li 1 , Sai-Wah Tsao 2 , Jen-Fu Chiu 1, 2 1 Department of Biochemistry/Open Laboratory of Tumor Molecular Biology, Shantou University College of Medicine, Shantou, Guangdong, China 2 School of Biomedical Sciences, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China * These authors have contributed equally to this work Correspondence to: Jen-Fu Chiu, email: jfchiu@hku.hk Sai-Wah Tsao, email: gswtsao@hku.hk Keywords: arsenic, benzo[α]pyrene, Warburg effect, oxidative phosphorylation, hypoxia Received: October 29, 2015     Accepted: April 29, 2016     Published: June 3, 2016 ABSTRACT Arsenic and benzo[α]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-1a 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.