xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction

Cobler, Lara; Zhang, Hui; Suri, Poojan; Park, Catherine; Timmerman, Luika

doi:10.18632/oncotarget.25794

Cited by 54 publications

(47 citation statements)

References 77 publications

(85 reference statements)

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“…4). These results corroborate a very recent report of xCT-KO in a breast cancer cell (MDA-MB-231) xenografts (37). However, our ability to extract MiaPaCa-2 xCT-KO Matrigel cell plugs at the end of the experiment revealed that surprisingly, some of the injected xCT-KO cells had remained viable for more than 3 weeks.…”

Section: Discussionsupporting

confidence: 91%

Genetic Ablation of the Cystine Transporter xCT in PDAC Cells Inhibits mTORC1, Growth, Survival, and Tumor Formation via Nutrient and Oxidative Stresses

et al. 2019

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Although chemoresistance remains a primary challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC), exploiting oxidative stress might offer novel therapeutic clues. Here we explored the potential of targeting cystine/glutamate exchanger (SLC7A11/xCT), which contributes to the maintenance of intracellular glutathione (GSH). Genomic disruption of xCT via CRISPR-Cas9 was achieved in two PDAC cell lines, MiaPaCa-2 and Capan-2, and xCT-KO clones were cultivated in the presence of N-acetylcysteine. Although several cystine/ cysteine transporters have been identified, our findings demonstrate that, in vitro, xCT plays the major role in intracellular cysteine balance and GSH biosynthesis. As a consequence, both xCT-KO cell lines exhibited amino acid stress with activation of GCN2 and subsequent induction of ATF4, inhibition of mTORC1, proliferation arrest, and cell death. Tumor xenograft growth was delayed but not suppressed in xCT-KO cells, which indicated both the key role of xCT and also the presence of additional mechanisms for cysteine homeostasis in vivo. Moreover, rapid depletion of intracellular GSH in xCT-KO cells led to accumulation of lipid peroxides and cell swelling. These two hallmarks of ferroptotic cell death were prevented by vitamin E or iron chelation. Finally, in vitro pharmacologic inhibition of xCT by low concentrations of erastin phenocopied xCT-KO and potentiated the cytotoxic effects of both gemcitabine and cisplatin in PDAC cell lines. In conclusion, our findings strongly support that inhibition of xCT, by its dual induction of nutritional and oxidative cellular stresses, has great potential as an anticancer strategy. Significance: The cystine/glutamate exchanger xCT is essential for amino acid and redox homeostasis and its inhibition has potential for anticancer therapy by inducing ferroptosis.

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Section: Discussionsupporting

confidence: 91%

Genetic Ablation of the Cystine Transporter xCT in PDAC Cells Inhibits mTORC1, Growth, Survival, and Tumor Formation via Nutrient and Oxidative Stresses

et al. 2019

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“…Cysteine uptake plays an important role in cancer by maintaining redox balance, and numerous studies have shown the efficacy of xCT inhibition on tumor growth 36,148,149 . Importantly, a recent study revealed that xCT suppression acts synergistically with the immunotherapeutic agent anti-CTLA-4 150 .…”

Section: Therapeutic Applications From Amino Acid Metabolismmentioning

confidence: 99%

Amino acids in cancer

et al. 2020

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Over 90 years ago, Otto Warburg's seminal discovery of aerobic glycolysis established metabolic reprogramming as one of the first distinguishing characteristics of cancer 1. The field of cancer metabolism subsequently revealed additional metabolic alterations in cancer by focusing on central carbon metabolism, including the citric acid cycle and pentose phosphate pathway. Recent reports have, however, uncovered substantial non-carbon metabolism contributions to cancer cell viability and growth. Amino acids, nutrients vital to the survival of all cell types, experience reprogrammed metabolism in cancer. This review outlines the diverse roles of amino acids within the tumor and in the tumor microenvironment. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, amino acid derivatives contribute to epigenetic regulation and immune responses linked to tumorigenesis and metastasis. Furthermore, in discussing the transporters and transaminases that mediate amino acid uptake and synthesis, we identify potential metabolic liabilities as targets for therapeutic intervention.

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“…xCT was related to radioresistance in human breast cancer and mouse melanoma cell lines [93,94]. CD98 contributed to radioresistance in head and neck squamous cell carcinoma [95].…”

Section: Mtor-dependent Antioxidant Mechanism In Solidmentioning

confidence: 99%

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

Woo

Lee

Jung

et al. 2019

Journal of Oncology

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Radiotherapy is widely used for the treatment of cancer patients, but tumor radioresistance presents serious therapy challenges. Tumor radioresistance is closely related to high levels of mTOR signaling in tumor tissues. Therefore, targeting the mTOR pathway might be a strategy to promote solid tumor sensitivity to ionizing radiation. Radioresistance is associated with enhanced antioxidant mechanisms in cancer cells. Therefore, examination of the relationship between mTOR signaling and antioxidant mechanism-linked radioresistance is required for effective radiotherapy. In particular, the effect of mTOR signaling on antioxidant glutathione induction by the Keap1-NRF2-xCT pathway is described in this review. This review is expected to assist in the identification of therapeutic adjuvants to increase the efficacy of radiotherapy.

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xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction

Cited by 54 publications

References 77 publications

Genetic Ablation of the Cystine Transporter xCT in PDAC Cells Inhibits mTORC1, Growth, Survival, and Tumor Formation via Nutrient and Oxidative Stresses

Genetic Ablation of the Cystine Transporter xCT in PDAC Cells Inhibits mTORC1, Growth, Survival, and Tumor Formation via Nutrient and Oxidative Stresses

Amino acids in cancer

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

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