Aims:
Lung cancer is the leading cause of
cancer death worldwide, and tobacco smoking is a recognized major risk factor for lung
tumor development. We analyzed the effect of tobacco-specific
nitrosamines (TSNAs) on human
lung adenocarcinoma metabolic reprogramming, an emergent hallmark of
carcinogenesis. Results: A series of in vitro and in vivo bioenergetic, proteomic, metabolomic, and
tumor biology studies were performed to analyze changes in
lung cancer cell metabolism and the consequences for hallmarks of
cancer, including
tumor growth,
cancer cell invasion, and redox signaling. The findings revealed that
nicotine-derived
nitrosamine ketone (NNK) stimulates mitochondrial function and promotes lung
tumor growth in vivo. These malignant properties were acquired from the induction of mitochondrial biogenesis induced by the upregulation and activation of the
beta-2 adrenergic receptors (β2-AR)-cholinergic
receptor nicotinic alpha 7 subunit (CHRNAα7)-dependent
nitrosamine canonical signaling pathway. The observed NNK metabolic effects were mediated by TFAM overexpression and revealed a key role for mitochondrial
reactive oxygen species and
Annexin A1 in
tumor growth promotion. Conversely, ectopic expression of the mitochondrial
antioxidant enzyme manganese superoxide dismutase rescued the reprogramming and malignant metabolic effects of exposure to NNK and overexpression of TFAM, underlining the link between NNK and mitochondrial redox signaling in
lung cancer. Innovation: Our findings describe the metabolic changes caused by NNK in a mechanistic framework for understanding how cigarette smoking causes
lung cancer. Conclusion: Mitochondria play a role in the promotion of
lung cancer induced by tobacco-specific
nitrosamines. Antioxid. Redox Signal. 36, 525-549.