Abstract 1726: CRM1 is overexpressed in lung tumorigenesis and represents an adjuvant target for lung cancer treatment

Abstract

Abstract In spite of extensive investigations, the molecular mechanisms of lung tumorigenesis have not been completely understood, and the effective therapy for lung cancer is in great demand. Studies have shown that chromosome region maintenance 1 (CRM1), a nuclear export receptor for various cancer-associated ‘cargo’ proteins, overexpressed in several human cancers. The objectives of the present study are to evaluate the involvement of CRM1 in lung carcinogenesis and lung cancer treatment. First, we have analyzed the importance of CRM1 overexpression in lung cancer development. We showed that CRM1 was overexpressed in lung tumor tissues from lung cancer patients and lung adenocarcinoma in mice induced by a tobacco carcinogen, as well as lung cancer cell lines. The increased CRM1 expression levels in these lung cancer tissues and cells were associated with an increased phosphorylation level at threonine residue 55 of the p53 protein. Furthermore, CRM1 overexpression in lung cancer cells seemed to be p53-dependent. Stable overexpression of CRM1 in BEAS-2B cells led to malignant cellular transformation and p53 cytoplasmic localization. Moreover, as compared to A549 cells, cancer-related genes significantly altered in A549 cells with stable CRM1 knockdown. Second, we have evaluated targeting CRM1 as an adjuvant therapy for lung cancer treatment using both in vitro and in vivo models. We found that CRM1-siRNA could inhibit A549 cell growth and A549 cells with stable CRM1 knockdown showed more pronounced cytotoxic effects to cisplatin than A549 cells. In addition, A549 cells treated with cisplatin and a low non-toxic dose of leptomycin B (a CRM1 inhibitor) had a remarkably enhanced cytotoxicity compared to cisplatin. This increased therapeutic effect from leptomycin B and cisplatin was further validated using an in vivo xenograft mouse model. The findings of this study reveal the significance of CRM1 in lung carcinogenesis and lung cancer adjuvant therapy. Citation Format: Weimin Gao, Chuanwen Lu, Lixia Chen, Phouthone Keohavong. CRM1 is overexpressed in lung tumorigenesis and represents an adjuvant target for lung cancer treatment. [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 1726. doi:10.1158/1538-7445.AM2015-1726