Abstract
Most tumors undergo metabolic reprogramming towards glycolysis, the so-called Warburg effect, to support growth and survival. Overexpression of IF1, the physiological inhibitor of the F0F1ATPase, has been related to this phenomenon and appears to be a relevant marker in cancer. Environmental contributions to cancer development are now widely accepted but little is known about the underlying intracellular mechanisms. Among the environmental pollutants humans are commonly exposed to, benzo[a]pyrene (B[a]P), the prototype molecule of polycyclic aromatic hydrocarbons (PAHs), is a well-known human carcinogen. Besides apoptotic signals, B[a]P can also induce survival signals in liver cells, both likely involved in cancer promotion. Our previous works showed that B[a]P elicited a Warburg-like effect, thus favoring cell survival. The present study aimed at further elucidating the molecular mechanisms involved in the B[a]P-induced metabolic reprogramming, by testing the possible involvement of IF1. We presently demonstrate, both in vitro and in vivo, that PAHs, especially B[a]P, strongly increase IF1 expression. Such an increase, which might rely on β2-adrenergic receptor activation, notably participates to the B[a]P-induced glycolytic shift and cell survival in liver cells. By identifying IF1 as a target of PAHs, this study provides new insights about how environmental factors may contribute to related carcinogenesis.
Highlights
The mitochondrial H+-ATP synthase, called F0F1ATPase or complex V, is a master regulator of energy production and cell fate[1,2,3]
We further demonstrate that the Inhibitory Factor 1 (IF1) up-regulation observed in vitro upon B[a]P exposure would rely on the activation of the β2 adrenergic receptor pathway, and that it would be determinant in both the glycolytic shift and cell survival elicited by this compound
High IF1 expression is correlated with liver cancer progression and gene expression related to glycolytic metabolism in human hepatocarcinoma
Summary
The mitochondrial H+-ATP synthase, called F0F1ATPase or complex V, is a master regulator of energy production and cell fate[1,2,3]. Besides its well-recognized physiological role in oxidative phosphorylation (OXPHOS) as the major cell producer of ATP, this enzyme has been implicated in the morphogenesis of mitochondrial cristae[4], in the formation of the mitochondrial permeability transition pore (mPTP) during cell death[5], and the metabolic reprogramming of tumor cells[6] Regarding this latter point, a decreased OXPHOS capacity and subsequent drop in ATP synthesis due to complex V inhibition, appears to be responsible for a metabolic shift towards aerobic glycolysis, which is better known as the Warburg effect[1]. A reverse activity of complex V upon B[a]P exposure, was previously suggested[23] As all these cell responses have been linked to IF1, the present study aimed at testing the impact of B[a]P on IF1 level, and at evaluating its role in the survival process elicited by this contaminant in the F258 rat liver epithelial cell line. We further demonstrate that the IF1 up-regulation observed in vitro upon B[a]P exposure would rely on the activation of the β2 adrenergic receptor pathway, and that it would be determinant in both the glycolytic shift and cell survival elicited by this compound
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
