Abstract 3843: Nrf2-keap1 axis: uncovers molecular profile in lung carcinoids

Abstract

Abstract Introduction. The Keap1/Nrf2 pathway is a master regulator of antioxidants and cellular stress re-sponses implicated in resistance of tumour cells against chemotherapeutic drugs. Recent data suggest that genetic and epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression in Non Small Cell Lung Cancer. At present, the data concerning the mechanism of alteration of Nrf2-Keap1 pathway in the Carcinoids of the lung remain almost incomplete. Materials and methods. Here we report a comprehensive molecular characterization of Keap1/Nrf2 axis in cell lines and 48 tissues from Lung Carcinoid affected patients by integrating data from altera-tions at DNA, transcript and protein levels. Results. An hypermethylation of the CpGs island located into the P1 promoter region of the KEAP1 was detected in 16 out of the 32 Typical Carcinoids (50%) and 8 out of the 16 Atypical Carcinoids (50%). No somatic mutations were detected both in the kelch-repeats region of the KEAP1 gene and in the Nhe2 domain of NFE2L2 gene, whereas LOH at the KEAP1 locus (19p13.2) was found in more than 50% of cases, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event in lung carcinoids. Decreased of the KEAP1 expression in methylated cancer cells induced greater nuclear accumulation of Nrf2, causing enhanced transcriptional xenobiotic metabolism enzymes. Conclusions. This is the first study to our knowledge that provides new insights into the mechanism of deregulation of Nrf2/Keap1 detoxification pathway in lung carcinoids. Loss of KEAP1 function leading to constitutive activation of Nrf2-mediated gene expression in cancer suggests that deregulation of the Keap1/Nrf2 system could play a pivotal role in the pathogenesis of carcinoids. Citation Format: Angelo Sparaneo, Annamaria la Torre, Domenico Trombetta, Leonarda Di Candia, Massimiliano Copetti, Teresa Balsamo, Evaristo Maiello, Paolo Graziano, Vito M. Fazio, Lucia A. Muscarella, Montse Sanchez-Cespedes. Nrf2-keap1 axis: uncovers molecular profile in lung carcinoids. [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 3843. doi:10.1158/1538-7445.AM2015-3843