Abstract A10: SLC7A11 contributes to the pathogenesis of lung cancer

Abstract

Abstract Introduction: Many tumors increase uptake and dependence on nutrients such as glucose, cysteine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer. Here, we investigated the function of SLC7A11 (xCT), a cystine/glutamate anti-porter, in the pathogenesis of lung cancer. Recently, we found xCT to be strongly overexpressed at the cell surface of lung cancers and began to investigate the mechanisms by which xCT may contribute to lung cancer progression. Methods: The expression of xCT and its related genes in 411 patients with non small cell lung cancer (NSCLC) were evaluated in publically available lung cancer gene expression datasets. The association between xCT expression and overall survival, stage of diseases were tested in tissue microarray datasets. Gain of function studies for xCT were undertaken in the normal airway epithelium cell lines (BEAS2B and 16HBE) to investigate the role of xCT in regulating cell metabolism, growth and survival in normal and malignant lung epithelial cells. Results: Our results shows that xCT proein is overexpressed in 38% of NSCLC patients. We also found that expression of xCT mRNA is strongly associated with disease stage (p<0.01), smoking history (p =0.0202) and overrall survival (p<0.01). Overexpression of xCT in normal airway epithelium cells (16HBE and BEAS2B) induces the colony formaion in soft agar and tumor formation in nude mice. Targeting these cells with xCT overexpression by sulfasalazine significantly reduced tumor burden in mice by 50%. Furthermore, the overexpresion of xCT promotes increased glucose consumption, glutamine consumption and lactate production. Conclusion: Our results demonstrate that xCT is highly expressed in a subset of NSCLCs. The induction of xCT in transformed aiway epithelial cells causes tumor formation in nude mice. The mechanism of malignant transformation involves the Warburg effect. Further investigation into the mechanisms of transformation may help in answering fundamental questions pertaining to how glutamate/cystine exchange contributes to lung cancer development and progression and also in establishing xCT as a potential novel therapeutic target in lung cancer. Citation Format: Xiangming Ji Ji, Jun Qian, Jamshedur Rahman, Brad Harris, Megan Hoeksema, Heidi Chen, Rosana Eisenberg, Jamey Young. SLC7A11 contributes to the pathogenesis of lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A10.