Genetic ablation of the cystine transporter xCT in PDAC cells inhibits mTORC1, growth, survival and tumor formation via nutrient and oxidative stresses
Boutaina Daher,Scott K. Parks,Jérôme Durivault,Yann Cormerais,Hanane Baidarjad,Eric Tambutté,Jacques Pouysségur,Milica Vučetić +7 more
TLDR
In vitro pharmacological 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 strongly support that inhibition ofxCT, by its dual induction of nutritional and oxidative cellular stresses, has great potential as an anticancer strategy.Abstract:
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.read more
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Ferroptosis: mechanisms, biology and role in disease.
TL;DR: In this paper, the authors provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of the potential therapeutic roles, and its pathological roles, together with a potential for therapeutic targeting.
Journal ArticleDOI
Cysteine depletion induces pancreatic tumor ferroptosis in mice.
Michael A. Badgley,Daniel M. Kremer,H. Carlo Maurer,H. Carlo Maurer,Kathleen E. DelGiorno,Ho-Joon Lee,Vinee Purohit,Irina Sagalovskiy,Alice Ma,Jonathan Kapilian,Christina E. M. Firl,Amanda R. Decker,Steve A. Sastra,Carmine F. Palermo,Leonardo R. Andrade,Peter Sajjakulnukit,Li Zhang,Zachary P. Tolstyka,Tal Hirschhorn,Candice Lamb,Tong Liu,Wei Gu,E. Scott Seeley,Everett Stone,George Georgiou,Uri Manor,Alina Iuga,Geoffrey M. Wahl,Brent R. Stockwell,Costas A. Lyssiotis,Kenneth P. Olive +30 more
TL;DR: This work shows that the import of oxidized cysteine (cystine) via system xC– is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality.
Journal ArticleDOI
Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy
TL;DR: Diverse regulatory mechanisms of SLC7A11 in cancer are summarized, ferroptosis-dependent and -independent functions of S LC7A 11 in promoting tumor development are discussed, the mechanistic basis of SLP11-induced nutrient dependency in cancer cells is explored, and therapeutic strategies to target SLC 7A11 are conceptualized.
Journal ArticleDOI
Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases
Xiaohua Song,Dingxin Long +1 more
TL;DR: There is still insufficient evidence for ferroptosis and Nrf2 regulatory networks in the field of neurodegenerative diseases, but the nuclear factor E2 related factor 2 (Nrf2/NFE2L2) has been proved to play a key role in neurodegenersative disease treatment and ferroPTosis regulation.
Journal ArticleDOI
The role of ROS in tumour development and progression
Eric C. Cheung,Karen H. Vousden +1 more
TL;DR: The responses to ROS are highly complex and dependent on multiple factors, including the types, levels, localization and persistence of ROS, as well as the origin, environment and stage of the tumours themselves.
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Yangchun Xie,Wen Hou,Xinxin Song,Yan Yu,Jin Huang,Xiaofang Sun,Rui Kang,Daolin Tang,Daolin Tang +8 more
TL;DR: Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity.
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