Abstract 2711: Regulation of the IGF-1R signaling by angiotensin signaling pathway

Abstract

Abstract Lung cancer is one of the most commonly diagnosed cancers in the world. Tobacco smoking is the most predominant risk factor for the development of lung cancer. Carcinogenic compounds in tobacco smoke are thought to be responsible for lung cancer, at least in part, by activating G-protein coupled receptor (GPCR)-mediated signaling pathways. GPCR signaling has been suggested to cross-talk with the IGF-1R signaling pathway, a key pathway for cell survival, transformation and growth. However, the mechanisms underlying the crosstalk between GPCR and IGF-1R signaling pathways remain poorly understood. Here we show that tobacco carcinogen (TC) contributes to the lung carcinogenesis by activating the angiotensin signaling and subsequent IGF-1R signaling pathways. We observed that a potent tobacco carcinogen, nitrosamine 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK, nicotine-derived nitrosamine ketone), induced transformed phenotypes, including foci formation, viability in the absence of growth factors, and anchorage-dependent and -independent colony formation, and activation of the IGF-1R in normal human bronchial epithelial cells. The NNK treatment also induced lung tumor formation in mice. Losartan, an angiotensin type-1 receptor blocker, and captopril, an angiotensin converting enzyme (ACE) inhibitor, disrupted NNK-induced IGF-1R activation and transformed phenotypes in normal human bronchial epithelial cells and reduced lung tumor formation in mice. These findings indicated that TC-induced angiotensin signaling pathway can enhance lung carcinogenesis by activating the IGF-1R signaling. Our results suggest that targeting IGF-1R by using angiotensin signaling inhibitors may be an effective strategy for the chemoprevention of lung cancer. Citation Format: Hye-Jin Boo, Hyun-Ji Jang, Yujin Jung, Hye-Young Min, Ho-Young Lee. Regulation of the IGF-1R signaling by angiotensin signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2711. doi:10.1158/1538-7445.AM2015-2711