xCT expression reduces the early cell cycle requirement for calcium signaling

Abstract

Calcium has long been recognized as an important regulator of cell cycle transitions although the mechanisms are largely unknown. A functional genomic screen has identified genes involved in the regulation of early cell cycle progression by calcium. These genes when overexpressed confer the ability to bypass the G1/S arrest induced by Ca 2+ -channel antagonists in mouse fibroblasts. Overexpression of the cystine-glutamate exchanger, xCT, had the greatest ability to evade calcium antagonist-induced cell cycle arrest. xCT carries out the rate limiting step of glutathione synthesis in many cell types and is responsible for the uptake of cystine in most human cancer cell lines. Functional analysis indicates that the cystine uptake activity of xCT overcomes the G1/S arrest induced by Ca 2+ -channel antagonists by bypassing the requirement for calcium signaling. Since cells overexpressing xCT were found to have increased levels and activity of the AP-1 transcription factor in G1, redox stimulation of AP-1 activity accounts for the observed growth of these cells in the presence of calcium channel antagonists. These results suggest that reduced calcium signaling impairs AP-1 activation and that xCT expression may directly affect cell proliferation.

The Novel Arsenical Darinaparsin Is Transported by Cystine Importing Systems

“…In addition, upregulation of xCT expression, cystine/cysteine uptake, and intracellular GSH levels have been associated with resistance to cancer therapy (Huang et al, 2005;Diaz et al, 2008). Indeed, the xCT-overexpressing HT1080 model cells used in these experiments are resistant to dihydropyridines and cobalt chloride (Lastro et al, 2008). Importantly, xCT expression is induced by both ATO and Dar, leading to cytoprotection against ATO, but leading to increased import for Dar.…”

“…To strengthen and expand our hypothesis beyond NB4 cells, we used several cell line models of non-APL malignancies. First, we used a previously characterized in vitro model of increased xCT activity, HT1080 human fibrosarcoma cells transduced with an empty retroviral vector or one directing the expression of xCT (Lastro et al, 2008). We compared and assessed apoptosis in the modified HT1080 cell lines following 48 hours of treatment with 2-5 mM Dar or DMAC.…”

“…The human colorectal cancer cell lines HCT 116 and RKO 2577 (provided by Dr. Raquel Aloyz) were cultured in RPMI 1640 media (HCT 116) or Eagle's modified essential medium (RKO 2577), supplemented with 10% fetal bovine serum. HT1080 human fibrosarcoma cells transduced with empty vector or xCT were described previously (Lastro et al, 2008) and were cultured in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum.…”

Burn injury induces the expression of cystine/glutamate transporter (xc−) in mouse T cells

“…Moreover, thermal injury causes defects in T cell signaling involving problems in Ca 2+ mobilization. A recent study demonstrated that xCT expression in mouse fibroblasts could bypass the G1/S arrest induced by Ca 2+ -channel antagonists [48,49]. Also, a recent study demonstrated increased splenic xCT expression a murine model of endotoxemia and sepsis which is commonly associated with thermal injury [30].…”

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

“…Most recent work suggested that xCT can directly affect cell proliferation through regulation of AP-1 activity (Lastro et al, 2008). AP-1 transcriptional activity is increased when xCT is overexpressed.…”