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.
Highlights
Benzo[α]pyrene and arsenic derivatives are ubiquitously distributed in our environment [1,2,3,4], leading to wide-spread human exposure [5,6,7,8,9,10]
transformed rat lung epithelial cell (TLEC) were characterized by a large nucleus, increased nucleus/cytoplasm ratio, and irregular size and shape, with movement starting with the formation of irregular cytoplasmic pseudopods (Figure 1C)
The tumorigenic properties of TLECs were studied in vivo
Summary
Benzo[α]pyrene and arsenic derivatives are ubiquitously distributed in our environment [1,2,3,4], leading to wide-spread human exposure [5,6,7,8,9,10]. Most cancer cells display upwww.impactjournals.com/oncotarget regulation of glycolysis for fast production of ATP. This phenomenon was discovered 80 years ago and termed the “Warburg effect” [20]. A change in glucose metabolism has been implicated as a key contributor to malignant progression [21,22,23] How this glycolytic switch happens, and whether it is a cause or a consequence has remained a matter of debate. Other reports reveal that some cancers are more sensitive to inhibition of OXPHOS than inhibition of glycolysis [27, 28], indicating aerobic glycolysis is not a must for cancer cells. Due to the heterogeneity and plasticity of cancer cells, it is possible that such cancer cells rely more heavily on OXPHOS under normoxic conditions, and switch to glycolysis under hypoxic conditions
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