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. 2018 Sep;37(36):5007-5019.
doi: 10.1038/s41388-018-0307-z. Epub 2018 May 23.

"V体育ios版" xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression

Xiangming Ji  1   2 , Jun Qian  1 , S M Jamshedur Rahman  1 , Peter J Siska  3 , Yong Zou  1 , Bradford K Harris  1 , Megan D Hoeksema  1 , Irina A Trenary  4 , Chen Heidi  5 , Rosana Eisenberg  6 , Jeffrey C Rathmell  3 , Jamey D Young  4 , Pierre P Massion  7   8
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"V体育ios版" xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression

Xiangming Ji (V体育平台登录) et al. Oncogene. 2018 Sep.

VSports手机版 - Abstract

Many tumors increase uptake and dependence on glucose, cystine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer research. Recent studies demonstrated that smoking could induce the expression of xCT (SLC7A11) in oral cancer cells, suggesting that overexpression of xCT may support lung tumor progression. We hypothesized that overexpression of xCT occurs in lung cancer cells to satisfy the metabolic requirements for growth and survival. Our results demonstrated that 1) xCT was highly expressed at the cytoplasmic membrane in non-small cell lung cancer (NSCLC), 2) the expression of xCT was correlated with advanced stage and predicted a worse 5-year survival, 3) targeting xCT transport activity in xCT overexpressing NSCLC cells with sulfasalazine decreased cell proliferation and invasion in vitro and in vivo and 4) increased dependence on glutamine was observed in xCT overexpressed normal airway epithelial cells. These results suggested that xCT regulate metabolic requirements during lung cancer progression and be a potential therapeutic target in NSCLC. VSports手机版.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
xCT is overexpressed in human NSCLC tumors and predicts worse overall survival. a The mRNA expression of xCT is significantly overexpressed in SCC and ADC compared with normal lung tissues in TCGA (p < 0.001). b Log-rank test demonstrated that the elevated xCT protein expression in TMA is correlated with shorter five-year survival (p = 0.003). c Representative images of IHC staining for xCT protein, and hematoxylin for nuclei. Top, two representative photomicrographs at ×100 magnification of tumor sections with stage III SCC and III ADC. A zoomed in ×200 magnification of a small area of the same sections in the top right corner showed membranous staining pattern of cancer cells. Bottom, representative photomicrographs at ×100 magnification of normal lung tissue from patients with lung cancer, which stained negative for xCT. d Western blots of xCT protein expression from normal human lung (N) and their paired tumor samples (T)
Fig. 2
Fig. 2
xCT suppression by shRNA inhibits proliferation and tumorigenicity of H520 in vitro and in vivo. a Cell proliferation assays reveal significant growth inhibition induced by xCT knockdown in H520 (n = 4). b Evidence for xCT knockdown in H520 cells to affect the amino acids consumption and excretion in media (n = 4). c The knockdown of xCT significantly decreases the glucose consumption in H520 cells. d The knockdown of xCT significantly decreases the lactate production in H520 cells (n = 4). e The knockdown of xCT promotes more oxidative intracellular condition in the H520 cells (n = 6). f The knockdown of xCT significantly decreases the glutamine dependency in H520 cells (n = 4). g Knockdown of xCT significantly reduces the H520 cell invasion compared with the H520_Ctrl by matrigel cell invasion assay (n = 3). h The effect of xCT knockdown on tumorigenicity in nude mice. Both H520_Ctrl (left flank) and H520_xCT_KD (right flank) cells were injected subcutaneously into the nude mice (n = 10). Tumor burden was monitored twice a week by caliper. Tumor size was calculated as 3.14 × (Min)2 × (Max)/6, where Min and Max were from (length, width, and depth of tumor measurements). All the tumors (mm3) were measured in both flanks of 10 mice
Fig. 3
Fig. 3
Targeting xCT in NSCLC by SASP. a xCT is highly expressed among different types of lung cancer cell lines. b Representative images of IHC staining for xCT protein in NSCLC cells, A549, H520, and H1869. c Cell proliferation assays reveals dose-dependent growth inhibition induced by SASP in A549 and H520 but not in H1869 NSCLC cells (n = 4). d Treatment of SASP reduces the tumor size in nude mice. Five million H520 cells were implanted into flanks of nude mice (n = 10). After two weeks, mice were randomly assigned into two groups. Tumor burden was monitored twice a week by caliper. Tumor size was calculated as 3.14(Min)2 × (Max)/6, where Min and Max were from length, width, and depth of tumor measurement. e H&E staining, immunohistochemical staining for Ki67, cleaved Caspase 3 and xCT in tumor formed by H520 in SASP treated or control mice
Fig. 4
Fig. 4
Overexpression of xCT promotes the proliferation and glutamine dependency of human normal airway epithelium cells. a, b Representative immunohistochemical staining for xCT protein expression in a section of normal airway epithelium cells A (16HBE) and B (BEAS2B). Overexpression of xCT promotes cell proliferation in 16HBE (c) and BEAS2B (d) (n = 4). Glutamine deprivation assays shows that xCT overexpression promotes the glutamine dependency in 16HBE (e) and BEAS2B (f) in 72 h (n = 4). g Western blot demonstrates that overexpression of xCT is associated with MYC and its downstream molecular pathways such as GLS1, BCL-xL, and Cyclin D1 overexpression in 16HBE and BEAS2B cells (n = 3). h Effects of xCT overexpression in BEAS2B cell cycle distribution. Representative flow cytometry profiles and the corresponding ratio of cells in G1, S, and G2 phase at serum starvation baseline and after 48 h (n = 3)
Fig. 5
Fig. 5
xCT overexpression induces metabolic reprogramming in normal airway epithelial cells. a Evidence of xCT overexpression in BEAS2B cells modifies the amino acids consumption and excretion in media (n = 4). The overexpression of xCT increases the glucose consumption (b) and lactate production (c) (n = 4). d The overexpression of xCT increases in GSH/GSSG ratio and promotes more reductive intracellular conditions in the BEAS2B cells (n = 6). e The overexpression of xCT reduces ROS in BEAS2B (n = 6). f Overexpression of xCT elevates the oxygen consumption rate (OCR) in BEAS2B cells. The plot of OCR showed over time with the addition of oligomycin (1 µM), mitochondrial uncoupler FCCP (1 µM), and electron transport inhibitors antimycin (0.5 mM) + rotenone (0.5 mM). Maximal respiration, proton leak, and coupled respiration were determined as indicated (n = 6)
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