Regulation of System xCT (SLC7A11) by ABL Kinases in Human Lung Cancer

The ABL family of non-receptor tyrosine kinases, ABL1 and ABL2, are upregulated in non-small cell lung cancer and promote lung cancer metastasis. Recent work has shown that ABL kinases promote lung cancer brain metastasis and colonization. Global transcriptome analysis of targets controlled by ABL kinases in lung cancer cells revealed SLC7A11 as being differentially regulated in ABL inhibited cells. SLC7A11 encodes the plasma membrane antiporter system xCT which has been shown to be overexpressed in cancerous cells. System xCT exports glutamate and imports cystine, an intermediate molecule in the cellular oxidative stress response mechanism. Real-time polymerase chain reaction (RTPCR) verified a reduction in SLC7A11 mRNA levels following ABL pharmacologic inhibition or genetic knockdown. Continued work is being done to reveal a reduction in cellular protein levels through protein isolation and western blotting. FACS analysis will be deployed to determine whether membrane-localized levels of SLC7A11 decrease upon ABL inhibition. Additionally, a glutamate assay kit will be utilized to determine whether export of glutamate by xCT is reduced in ABL knockdown cells relative to control. The ultimate goal of this project is to understand if ABL kinases promote SLC7A11 expression in order to alter the brain microenvironment and promote tumor colonization.