Increased xCT Expression Correlates With Tumor Invasion and Outcome in Patients With Glioblastomas

Takeuchi, Satoru; Wada, Koichiro; Toyo’oka, Toshimasa; Shinomiya, Nariyoshi; Shimazaki, Hideyuki; Nakanishi, Kuniaki; Nagatani, Kimihiro; Otani, Naoki; Osada, Hideo; Uozumi, Yoichi; Matsuo, Hirotaka; Nawashiro, Hiroshi

doi:10.1227/neu.0b013e318276b2de

Cited by 82 publications

(69 citation statements)

References 37 publications

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“…Cysteine plays an important role in glutathione (GSH) synthesis, which is indispensable for maintaining intracellular redox balance and drug metabolism (23)(24)(25). xCT is highly expressed in several human cancers, and its expression is associated with malignancy, drug resistance, and poor survival in patients (21,(25)(26)(27)(28). In addition, a CD44 variant promotes tumor growth by stabilizing the xCT protein (29).…”

mentioning

confidence: 99%

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Mimura

Okada

et al. 2014

Molecular and Cellular Biology

163

153

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The ubiquitin-proteasome pathway degrades ubiquitinated proteins to remove damaged or misfolded protein and thus plays an important role in the maintenance of many important cellular processes. Because the pathway is also crucial for tumor cell growth and survival, proteasome inhibition by specific inhibitors exhibits potent antitumor effects in many cancer cells. xCT, a subunit of the cystine antiporter system x c ؊ , plays an important role in cellular cysteine and glutathione homeostasis. Several recent reports have revealed that xCT is involved in cancer cell survival; however, it was unknown whether xCT affects the cytotoxic effects of proteasome inhibitors. In this study, we found that two stress-inducible transcription factors, Nrf2 and ATF4, were upregulated by proteasome inhibition and cooperatively enhance human xCT gene expression upon proteasome inhibition. In addition, we demonstrated that the knockdown of xCT by small interfering RNA (siRNA) or pharmacological inhibition of xCT by sulfasalazine (SASP) or (S)-4-carboxyphenylglycine (CPG) significantly increased the sensitivity of T24 cells to proteasome inhibition. These results suggest that the simultaneous inhibition of both the proteasome and xCT could have therapeutic benefits in the treatment of bladder tumors.

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mentioning

confidence: 99%

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Mimura

Okada

et al. 2014

Molecular and Cellular Biology

163

153

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“…The xCT light chain of the system x c Ϫ antiporter is overexpressed in glioblastoma, hepatocellular carcinoma, and pancreatic cancer and has been utilized as a biomarker for neoplastic disease (43)(44)(45). A splice variant of CD44, designated CD44v, has been reported to stabilize xCT protein in cancer cells, increase GSH biosynthesis, and increase defense against reactive oxygen species (33).…”

Section: Discussionmentioning

confidence: 99%

Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes

Tsujita

Peirce

Baird

et al. 2014

Molecular and Cellular Biology

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“…11,12 As such, glutamate reportedly promotes glioma cell growth 13 and has been linked to tissue destruction 14 and tumorassociated epilepsy. 15 Studies in glioma cells have shown that system X c − is upregulated under oxidative stress, 16 and Takeuchi et al 17 reported that increased X c − expression in human GBMs was associated with a shorter survival. Intriguingly, sulfasalazine (SAS), a drug approved for treatment of rheumatoid arthritis 18 and inflammatory bowel diseases, 19 has been shown to block the X c − antiport system, thereby inhibiting glutamate release.…”

Section: Introductionmentioning

confidence: 99%

Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc−, leading to glutathione depletion

et al. 2015

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Glioblastomas (GBMs) are aggressive brain tumors that always recur after radiotherapy. Cystine, mainly provided by the system X(c)(-) antiporter, is a requirement for glioma cell synthesis of glutathione (GSH) which has a critical role in scavenging free radicals, for example, after radiotherapy. Thus, we hypothesized that the X(c)(-)-inhibitor sulfasalazine (SAS) could potentiate the efficacy of radiotherapy against gliomas. Here, we show that the catalytic subunit of system X(c)(-), xCT, was uniformly expressed in a panel of 30 human GBM biopsies. SAS treatment significantly reduced cystine uptake and GSH levels, whereas it significantly increased the levels of reactive oxygen species (ROS) in glioma cells in vitro. Furthermore, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death, whereas adding the antioxidant N-acetyl-L-cysteine (NAC) reversed cell death. Moreover, SAS and gamma knife radiosurgery (GKRS) synergistically prolonged survival in nude rats harboring human GBM xenografts, compared with controls or either treatment alone. In conclusion, SAS effectively blocks cystine uptake in glioma cells in vitro, leading to GSH depletion and increased ROS levels, DNA damage and cell death. Moreover, it potentiates the anti-tumor efficacy of GKRS in rats with human GBM xenografts, providing a survival benefit. Thus, SAS may have a role as a radiosensitizer to enhance the efficacy of current radiotherapies for glioma patients.

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Increased xCT Expression Correlates With Tumor Invasion and Outcome in Patients With Glioblastomas

Abstract: These findings suggest that xCT is an independent predictive factor in GBMs.

Cited by 82 publications

References 37 publications

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition

Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes

Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc−, leading to glutathione depletion

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