Abstract
Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).
Highlights
Close interconnections between energy metabolism and cell fate have been reported in which mitochondria play a crucial role, notably through a number of death effectors and the control of organic acid balances[3,4]
Our study revealed that B[a]P induced a metabolic reprogramming that involved the activation of NHE115,23, and that it led to the appearance of an epithelial-mesenchymal transition (EMT) phenotype
In order to identify the pathways that were differentially affected by exposure to B[a]P, we performed single-sample gene set enrichment analysis projection as a hypothesis-generating gene set identification tool. ssGSEA analysis revealed that the expression of an OXPHOS-related gene set was globally down-regulated, in contrast to glycolysis and xenobiotic metabolism-related genes which were up-regulated, indicating a B[a]P-induced metabolic reprogramming in hepatic cells (Supplementary Fig. S1)
Summary
Close interconnections between energy metabolism and cell fate have been reported in which mitochondria play a crucial role, notably through a number of death effectors and the control of organic acid balances[3,4]. Environmental carcinogens are among the various factors which might favor a high Δψm and metabolic reprogramming. Δψm increased following activation of the aryl hydrocarbon receptor (AhR) by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in murine hepatoma Hepa1c1c7 cells[9]. It remains to be determined whether glycolytic reprogramming occurs following activation of the AhR. Activation of the Na+/H+ exchanger 1 (NHE1) by B[a]P leads to intracellular alkalinization[15], an event known to play a role in metabolic reprogramming and malignant transformation[19]. Considering the B[a]P-induced hyperpolarization of F258 cells, we here investigated the effects of this carcinogen on energy metabolism of these cells. Our study revealed that B[a]P induced a metabolic reprogramming that involved the activation of NHE115,23, and that it led to the appearance of an epithelial-mesenchymal transition (EMT) phenotype
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
