Pharmacogenomic Approach Reveals a Role for the x_c⁻Cystine/Glutamate Antiporter in Growth and Celastrol Resistance of Glioma Cell Lines

Abstract

The x cϪ cystine/glutamate antiporter has been implicated in GSH-based chemoresistance because it mediates cellular uptake of cystine/cysteine for sustenance of intracellular GSH levels. Celastrol, isolated from a Chinese medicinal herb, is a novel heat shock protein 90 (Hsp90) inhibitor with potent anticancer activity against glioma in vitro and in vivo. In search of correlations between growth-inhibitory potency of celastrol in NCI-60 cell lines and microarray expression profiles of most known transporters, we found that expression of SLC7A11,

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

“…As to potential glioma therapy, system X c À emerges as a promising target (Chung et al, 2005;Savaskan et al, 2008;Chung and Sontheimer, 2009;Pham et al, 2010). Both components of system X c À (xCT and CD98) have shown to be transcriptionally upregulated in glioma specimens and interference with system X c À may disrupt two major pathophysiological properties of glioma cells: (1) the ability to induce neurodegeneration and (2) the ability to incorporate high levels of cystine required for rapid proliferation.…”

“…Both components of system X c À (xCT and CD98) have shown to be transcriptionally upregulated in glioma specimens and interference with system X c À may disrupt two major pathophysiological properties of glioma cells: (1) the ability to induce neurodegeneration and (2) the ability to incorporate high levels of cystine required for rapid proliferation. Although glioma cells appear to be highly dependent on system X c À -mediated cystine incorporation required for glutathione production and thus the scavenging of reactive oxygen species (Chung et al, 2005;Chung and Sontheimer, 2009;Pham et al, 2010), normal cells might be less vulnerable. This notion is supported by genetic deletion studies, that is, xCT-deficient mice are healthy in appearance and fertile (Sato et al, 2005;Shih et al, 2006;Liu et al, 2007).…”

“…Moreover, resistance of tumor cells to a variety of anticancer drugs is often associated with increased glutathione levels (Huang et al, 2005). Hence, interference with system X c À activity may sensitize glioma and other neoplastic cells for drug treatment as shown for Hsp90 inhibitors (Huang et al, 2005;Pham et al, 2010). In line with these findings, xCT knockdown reduced glioma cell proliferation solely under serum-deprived conditions (Figures 2b and c), suggesting that reduced cystine incorporation sensitize glioma cells to further oxidative stress caused by serum deprivation (Zhuge and Cederbaum, 2006).…”

Specific PET Imaging of xC− Transporter Activity Using a 18F-Labeled Glutamate Derivative Reveals a Dominant Pathway in Tumor Metabolism

“…Glutamate levels dropped within 3 hours which was paralleled by a reduced rate of [ À , the transporter (subunit) density and activity at protein level as well as glutamate concentrations are currently ongoing. Previously published data indicate the importance of system x C À for mediating chemoresistance of melphalan, cisplatin, irinotecan, and celastrol (34)(35)(36)(37)(38). In addition, an interaction of the xCT subunit of system x C À with a variant of the cancer stem cell marker CD44 was published recently.…”

Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

“…In addition to promoting tumor growth via mechanisms involving antioxidant machinery both inside and outside the cells and autocrine glutamate signaling, SLC7A11 also induces chemoresistance to selective drugs (28,(32)(33)(34). The underlying mechanism in this process also involves the ability of the transporter to modulate oxidative stress.…”