The tobacco-specific carcinogen NNK induces pulmonary tumorigenesis via nAChR/Src/STAT3-mediated activation of the renin-angiotensin system and IGF-1R signaling

Abstract

The renin-angiotensin (RA) system has been implicated in lung tumorigenesis without detailed mechanistic elucidation. Here, we demonstrate that exposure to the representative tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) promotes lung tumorigenesis through deregulation of the pulmonary RA system. Mechanistically, NNK binding to the nicotinic acetylcholine receptor (nAChR) induces Src-mediated signal transducer and activator of transcription 3 (STAT3) activation, resulting in transcriptional upregulation of angiotensinogen (AGT) and subsequent induction of the angiotensin II (AngII) receptor type 1 (AGTR1) signaling pathway. In parallel, NNK concurrently increases insulin-like growth factor 2 (IGF2) production and activation of IGF-1R/insulin receptor (IR) signaling via a two-step pathway involving transcriptional upregulation of IGF2 through STAT3 activation and enhanced secretion from intracellular storage through AngII/AGTR1/PLC-intervened calcium release. NNK-mediated crosstalk between IGF-1R/IR and AGTR1 signaling promoted tumorigenic activity in lung epithelial and stromal cells. Lung tumorigenesis caused by NNK exposure or alveolar type 2 cell-specific Src activation was suppressed by heterozygous Agt knockout or clinically available inhibitors of the nAChR/Src or AngII/AGTR1 pathways. These results demonstrate that NNK-induced stimulation of the lung RA system leads to IGF2-mediated IGF-1R/IR signaling activation in lung epithelial and stromal cells, resulting in lung tumorigenesis in smokers.

Lung cancer: an opportunity to repurpose available drugs

A cellular signaling pathway primarily known for modulating blood pressure also drives the progression of lung cancers arising from tobacco use. Dysfunction in the renin-angiotensin system can lead to hypertension, and many patients are treated with drugs targeting this signaling pathway. The renin-angiotensin system is also involved in certain cancers, and researchers led by Ho-Young Lee at Seoul National University, South Korea, have shown how a tobacco-derived carcinogen called NNK promotes lung cancer via this pathway. Working with cultured cells and animal models, the researchers showed that NNK stimulates production of angiotensin in respiratory tissues, resulting in IGF2 secretion. The IGF-1R signaling activation ultimately leads to transformation of pulmonary epithelial cells into cancerous ones. Antihypertensive drugs that act on the renin-angiotensin pathway suppressed NNK-mediated tumorigenesis in mice, highlighting the possibility of preventing lung cancer with existing drugs.