The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival

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).

Role for the ATPase inhibitory factor 1 in the environmental carcinogen-induced Warburg phenotype

“…As B[a]P was reported to trigger a mitochondrial matrix acidification, from approximately 8 to 6.5, in F258 cells 22 , this could explain the appearance of a 24 kDa band presently detected after electrophoresis, thus revealing the presence of active IF1 dimers. Despite the IF1 up-regulation and dimer appearance, only a trend towards decrease for complex V activity was found (decrease by about 12%; data not shown).…”

Nrf2 and AhR in metabolic reprogramming after contaminant exposure

“…Mitochondria play an important role in oxidative stress upon AhR activation by environmental contaminants, with a AhR-dependent ROS production, a mitochondrial membrane hyperpolarization, a mitochondrial matrix acidification and a decrease in mitochondrial electron transport chain activity in liver cells [29][30][31]. AhR was demonstrated to interact with a subunit of the ATPase synthase M A N U S C R I P T…”

“…We recently showed that B[a]P-induced mitochondrial dysfunction occurs in parallel with a Warburg-like metabolic shift characterized by a reduced cell respiration and an increased lactate production. These changes were associated with alterations in the tricarboxylic acid cycle, which likely involve a reduced activity of the mitochondrial complex II [29].…”

“…These cellular effects are associated with a metabolic reprogramming characterized by a reduced cell respiration, an increased lactate production, and an increase of pentose phosphate pathway activity that is known to produce anti-oxidant species such as NAPDH. B[a]P exposure also leads to mitochondrial dysfunction with a mitochondrial hyperpolarization and alterations in the tricarboxylic acid cycle associated with a Warburg-like metabolic reprogramming [29,31]. When considering that AhR also mediates B[a]P bioactivation and the production of reactive metabolites and ROS, the cellular survival sustained by the metabolic reprogramming would increase genome instability and mutagenicity.…”

The European Environmental Mutagenesis and Genomics Society Annual Meeting, 14–18 August 2016, Copenhagen, Denmark

“…Interestingly, interactions with Ah receptor are involved in several of these processes including immunosuppression, modification of proliferative and apoptotic pathways and up‐regulate cellular migration of cancerous cells and epithelial mesenchymal transition . Furthermore, AhR ligands also modulate the endogenous metabolism of glucose, lipids and amino acids . Most importantly, chemicals often act via several mechanisms.…”