Cystine-Glutamate Transporter SLC7A11 Mediates Resistance to Geldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin

Liu, Ruqing; Blower, Paul E.; Pham, Anh-Nhan; Fang, Jia‐Long; Dai, Zunyan; Wise, Carolyn; Green, Bridgette; Teitel, Candee H.; Ning, Baitang; Ling, Wenhua; Lyn‐Cook, Beverly; Kadlubar, Fred F.; Sadée, Wolfgang; Huang, Ying

doi:10.1124/mol.107.039644

Cited by 33 publications

(29 citation statements)

References 38 publications

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“…The SLC7A11 and SLC3A2 genes, encoding the heterodimeric amino acid transporter x À c , have been implicated in chemoresistance, by supplying cystine to the cell for glutathione synthesis (28). We experimentally confirmed that the x À c transporter confers resistance selectively to GA analogues with methoxy group or unsubstituted at C17 position, but not to analogues with amino group at the C17 position (29). Thus, using pharmacogenomics approach we have identified that, multiple transporters, either directly (by substrate-transporter interaction) or indirectly (by increasing glutathione levels), may contribute to tumors' sensitivity and resistance to GA analogues.…”

Section: Discussionsupporting

confidence: 66%

Pharmacogenomics Approach Reveals MRP1 (ABCC1)-Mediated Resistance to Geldanamycins

et al. 2008

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Section: Discussionsupporting

confidence: 66%

Pharmacogenomics Approach Reveals MRP1 (ABCC1)-Mediated Resistance to Geldanamycins

et al. 2008

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“…10). In support of this idea, system x c -inhibitors can lead to intracellular GSH depletion and reverse the multidrug resistance of cells to certain anticancer drugs in vitro (45,93,150,206). In another study, it was demonstrated that system x c -specifically mediates resistance to anticancer drugs that produce high amounts of ROS, such as geldanamycin and celastrol (150,206).…”

Section: System X C 2 In Health and Diseasementioning

confidence: 77%

The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

Lewerenz

Hewett

Huang

et al. 2013

Antioxidants & Redox Signaling

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The antiporter system x c -imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1:1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system x c -is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system x c -, including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system x c -. Moreover, the roles of system x c -in regulating GSH levels, the redox state of the extracellular cystine/cysteine redox couple, and extracellular glutamate levels are discussed. In vitro, glutamate-mediated system x c -inhibition leads to neuronal cell death, a paradigm called oxidative glutamate toxicity, which has successfully been used to identify neuroprotective compounds. In vivo, xCT has a rather restricted expression pattern with the highest levels in the CNS and parts of the immune system. System x c -is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system x c -in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS. Antioxid. Redox Signal. 18, 522-555.

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“…The cystine/glutamate exchanger x c -is involved in the transport of cystine, and is a key regulator of cellular GSH levels mediating chemoresistance to cytotoxic agents [16,37] . Inhibition of the cystine transporter with the aim of depleting GSH has been suggested as a therapeutic potential in treatment of human lymphomas and leukemias [14,38,39] , breast cancers [12,40] and gliomas [41,42] .…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Cystine Transporter x<sub>c</sub><sup>–</sup> by Irinotecan in Human Head and Neck Cancer FaDu Xenografts

et al. 2010

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Background: The purpose of this study was: (1) to document the critical requirement of cystine for growth of human tumor cells in vitro, and (2) to determine the effect of the anticancer agent irinotecan on the cystine transporter x_c^– in head and neck FaDu xenografts. Methods: Cell growth was measured by sulforhodamine B assay. xCT protein, glutathione (GSH) and DNA damage were determined using Western blot, spectrophotometry, and immunohistochemistry, respectively. Results: Depletion of cystine from the medium inhibited tumor cell growth. Treatment of FaDu tumor with a therapeutic dose of irinotecan resulted in depression of xCT protein levels, leading to tumor growth retardation and downregulation of GSH with increased reactive oxygen species (ROS). The accumulation of ROS correlated with increased DNA damage as evidenced by increased H2AX. Conclusion: Depression of xCT protein by irinotecan resulted in downregulation of GSH and increase in ROS, which could be the other possible mechanisms of DNA damage by irinotecan.

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Cystine-Glutamate Transporter SLC7A11 Mediates Resistance to Geldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin

Cited by 33 publications

References 38 publications

Pharmacogenomics Approach Reveals MRP1 (ABCC1)-Mediated Resistance to Geldanamycins

Pharmacogenomics Approach Reveals MRP1 (ABCC1)-Mediated Resistance to Geldanamycins

The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

Downregulation of Cystine Transporter x<sub>c</sub><sup>–</sup> by Irinotecan in Human Head and Neck Cancer FaDu Xenografts

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Cystine-Glutamate Transporter SLC7A11 Mediates Resistance to Geldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin

Cited by 33 publications

References 38 publications

Pharmacogenomics Approach Reveals MRP1 (ABCC1)-Mediated Resistance to Geldanamycins

Pharmacogenomics Approach Reveals MRP1 (ABCC1)-Mediated Resistance to Geldanamycins

The Cystine/Glutamate Antiporter System xc−in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

Downregulation of Cystine Transporter x<sub>c</sub><sup>–</sup> by Irinotecan in Human Head and Neck Cancer FaDu Xenografts

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The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities