SLC7A11 negatively associates with mismatch repair gene expression and endows glioblastoma cells sensitive to radiation under low glucose conditions

Hu, Nan; Hu, Weihua; Zhou, Shaolong; Yang, Zhuo; Liang, Wan; Yang, Ruyi; Li, Minghe; Zhou, Jing; Li, Zian; Fu, Xudong; Wang, Xinjun

doi:10.4149/neo_2021_210327n410

Cited by 7 publications

(7 citation statements)

References 30 publications

(37 reference statements)

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“…Cancer cells with SLC7A11 high highly depend on specific amino acids, such as glucose and glutamine, which may force the establishment of a novel therapeutic strategy to target cancer-specific metabolic vulnerabilities. In SLC7A11 high GBM cells, glucose restriction decreases mismatch repair genes and increases double-strand breaks, making cancer cells more susceptible to radiation therapy [ 81 ]. CD44v-expressing stem-like head and neck squamous cell carcinoma (HNSCC) cells retain metabolic reprogramming toward increased glutaminolysis, which renders the cells more sensitive to xCT inhibitors with the combination of glutamate dehydrogenase (GDH) inhibition [ 82 ].…”

Section: Role Of Slc7a11 Linking Cysteine Redox Signaling To Cancer M...mentioning

confidence: 99%

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer

Lee

Roh

2022

Antioxidants

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SLC7A11 is a cell transmembrane protein composing the light chain of system xc−, transporting extracellular cystine into cells for cysteine production and GSH biosynthesis. SLC7A11 is a critical gateway for redox homeostasis by maintaining the cellular levels of GSH that counter cellular oxidative stress and suppress ferroptosis. SLC7A11 is overexpressed in various human cancers and regulates tumor development, proliferation, metastasis, microenvironment, and treatment resistance. Upregulation of SLC7A11 in cancers is needed to adapt to high oxidative stress microenvironments and maintain cellular redox homeostasis. High basal ROS levels and SLC7A11 dependences in cancer cells render them vulnerable to further oxidative stress. Therefore, cyst(e)ine depletion may be an effective new strategy for cancer treatment. However, the effectiveness of the SLC7A11 inhibitors or cyst(e)inase has been established in many preclinical studies but has not reached the stage of clinical trials for cancer patients. A better understanding of cysteine and SLC7A11 functions regulating and interacting with redox-active proteins and their substrates could be a promising strategy for cancer treatment. Therefore, this review intends to understand the role of cysteine in antioxidant and redox signaling, the regulators of cysteine bioavailability in cancer, the role of SLC7A11 linking cysteine redox signaling in cancer metabolism and targeting SLC7A11 for novel cancer therapeutics.

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Section: Role Of Slc7a11 Linking Cysteine Redox Signaling To Cancer M...mentioning

confidence: 99%

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer

Lee

Roh

2022

Antioxidants

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“…As mentioned before, this system is important in ferroptosis because its ability to regulate intracellular cystine intake and subsequently cysteine availability [92]. In GBM, xCT plays an important role in tumour survival and progression [93]. In the study of Takeuchi et al, including 40 GBM patients, xCT expres-sion was correlated with the clinical outcome.…”

Section: The Xct Systemmentioning

confidence: 94%

Ferroptosis Involvement in Glioblastoma Treatment

et al. 2022

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Glioblastoma multiforme (GBM) is one of the deadliest brain tumors. Current standard therapy includes tumor resection surgery followed by radiotherapy and chemotherapy. Due to the tumors invasive nature, recurrences are almost a certainty, giving the patients after diagnosis only a 12–15 months average survival time. Therefore, there is a dire need of finding new therapies that could potentially improve patient outcomes. Ferroptosis is a newly described form of cell death with several implications in cancer, among which GBM. Agents that target different molecules involved in ferroptosis and that stimulate this process have been described as potentially adjuvant anti-cancer treatment options. In GBM, ferroptosis stimulation inhibits tumor growth, improves patient survival, and increases the efficacy of radiation and chemotherapy. This review provides an overview of the current knowledge regarding ferroptosis modulation in GBM.

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“…Cancer cells with higher SLC7A11 expression levels may be highly dependent on certain nutrients-such as glucose and glutamine-for survival, which can inform therapeutic strategies to target these cancer-specific metabolic vulnerabilities. Under glucose restriction, the overexpression of SLC7A11 significantly decreases the mismatch repair gene, shows an increased level of double-strand breaks, and increases sensitivity to radiotherapy in GBM cells [157]. Furthermore, the cytotoxicity of the SLC7A11 inhibitor sulfasalazine in CD44v-expressing stem-like head and neck squamous cells is related to glutamine uptake and GDH-related α-KG production.…”

Section: Nutrient Dependencymentioning

confidence: 99%

The Role of SLC7A11 in Cancer: Friend or Foe?

Sun

et al. 2022

Cancers

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SLC7A11 controls the uptake of extracellular cystine in exchange for glutamate at a ratio of 1:1, and it is overexpressed in a variety of tumours. Accumulating evidence has shown that the expression of SLC7A11 is fine-tuned at multiple levels, and plays diverse functional and pharmacological roles in tumours, such as cellular redox homeostasis, cell growth and death, and cell metabolism. Many reports have suggested that the inhibition of SLC7A11 expression and activity is favourable for tumour therapy; thus, SLC7A11 is regarded as a potential therapeutic target. However, emerging evidence also suggests that on some occasions, the inhibition of SLC7A11 is beneficial to the survival of cancer cells, and confers the development of drug resistance. In this review, we first briefly introduce the biological properties of SLC7A11, including its structure and physiological functions, and further summarise its regulatory network and potential regulators. Then, focusing on its role in cancer, we describe the relationships of SLC7A11 with tumourigenesis, survival, proliferation, metastasis, and therapeutic resistance in more detail. Finally, since SLC7A11 has been linked to cancer through multiple approaches, we propose that its contribution and regulatory mechanism require further elucidation. Thus, more personalised therapeutic strategies should be adapted when targeting SLC7A11.

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SLC7A11 negatively associates with mismatch repair gene expression and endows glioblastoma cells sensitive to radiation under low glucose conditions

Cited by 7 publications

References 30 publications

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer

Ferroptosis Involvement in Glioblastoma Treatment

The Role of SLC7A11 in Cancer: Friend or Foe?

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