Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine

Poursaitidis, Ioannis; Wang, Xiaomeng; Crighton, Thomas; Labuschagne, Christiaan F.; Mason, David; Cramer, Shira L.; Triplett, Kendra; Roy, Rajat; Pardo, Olivier E.; Seckl, Michael J.; Rowlinson, Scott W.; Stone, Everett; Lamb, Richard F.

doi:10.1016/j.celrep.2017.02.054

Cited by 217 publications

(167 citation statements)

References 38 publications

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“…One agent that can trigger ferroptosis in xenograft tumors in vivo are engineered nanoparticles that deliver high concentrations of iron into the cell . Enzymatic depletion of plasma cysteine and cystine using an engineered enzyme, cyst(e)inase, can also reduce tumor growth in various xenograft models of cancer in mice, but does not result in regressions . Whether these two agents cause GPX4 inactivation and how lipid peroxidation is affected at the molecular level are not clear.…”

Section: Gpx4 Lipid Peroxidation and Ferroptosis In Development Andmentioning

confidence: 99%

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

2019

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Oxygen is necessary for aerobic metabolism but can cause the harmful oxidation of lipids and other macromolecules. Oxidation of cholesterol and phospholipids containing polyunsaturated fatty acyl chains can lead to lipid peroxidation, membrane damage, and cell death. Lipid hydroperoxides are key intermediates in the process of lipid peroxidation. The lipid hydroperoxidase glutathione peroxidase 4 (GPX4) converts lipid hydroperoxides to lipid alcohols, and this process prevents the iron (Fe2+)‐dependent formation of toxic lipid reactive oxygen species (ROS). Inhibition of GPX4 function leads to lipid peroxidation and can result in the induction of ferroptosis, an iron‐dependent, non‐apoptotic form of cell death. This review describes the formation of reactive lipid species, the function of GPX4 in preventing oxidative lipid damage, and the link between GPX4 dysfunction, lipid oxidation, and the induction of ferroptosis.

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Section: Gpx4 Lipid Peroxidation and Ferroptosis In Development Andmentioning

confidence: 99%

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

2019

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“…Recent studies have indicated that therapy-resistant and mesenchymal tumor cells, two features seen in the recurrent tumor cells, become more sensitive to cell death induced by cystine deprivation 17, 39 . Cystine is imported into mammalian cells in exchange of the export of glutamate via the xCT transporter 40 , which can be blocked by xCT inhibitors, such as the erastin or sulfasalazine 41, 42, 43 .…”

Section: Resultsmentioning

confidence: 99%

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

Lin

Mabe

Lin

et al. 2019

Preprint

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26The molecular and genetic basis of tumor recurrence is complex and poorly 27 understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, 28 its expression is frequently suppressed in primary tumors. In a transcriptome profiling 29 between primary and recurrent breast tumor cells from a murine model of breast 30 cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is 31 dramatically re-expressed in recurrent breast tumor cells by an epigenetic mechanism. 32 Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced 33 clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the 34 activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic 35 RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, 36 high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on 37 extracellular cystine and undergo programmed necrosis upon cystine deprivation. The 38 induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that 39 paradoxically confers on tumors both growth advantage and necrotic vulnerability, 40 providing potential strategies to eradicate recurrent tumors. 41 42 43 44 45 46 47 48While significant progress has been made for the diagnosis and treatment of 52 primary tumors, the emergence of recurrent tumors after the initial response to 53 treatments still poses significant clinical challenges. Recurrent breast tumors are 54 generally incurable and unresponsive to the treatments effective for primary tumors 1 . 55Several factors have shown to be associated with breast tumor recurrence, including 56 the age when primary tumor is diagnosed 2, 3 , lymph node status, tumor size, 57 histological grade 4, 5, 6 , the status of estrogen receptor (ER), progesterone receptor 58 (PR) and the expression of human epidermal growth factor receptor 2 (HER2) 7, 8, 9 . 59 However, the molecular and genetic events that lead to tumor recurrence remain 60 largely unknown. 61To study the mechanism of tumor recurrence, genetically engineered mouse 62 (GEM) models of recurrent breast cancers have been established. Utilizing the 63 doxycycline-inducible system, the expression of specific oncogenes can be 64 conditionally expressed and withdrawn in the mammary gland 10, 11, 12, 13, 14 . In the bi-65 transgenic mice expressing an MMTV-rtTA (MTB) and inducible Neu (homolog of 66 HER2) oncogene (TetO-neu; TAN), mammary adenocarcinomas can be induced by 67 the administration of doxycycline and regressed after doxycycline withdrawal 10, 11, 12, 68 13, 14 . Importantly, the recurrent tumors will eventually emerge in most mice after the 69 expression of the oncogene is turned off 10, 11, 12, 13, 14 . This tumor recurrent model 70 bears significant similarities to human breast cancer recurrence in several important 71 ways: (1) Tumor recurrence occurs over a long timeframe relative to the lifespan of 72 the mouse, similar to the timing of recurrences in h...

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“…Inhibition of ferroptosis is potential to facilitate sorafenib (an EGFR inhibitor) resistance to cancer cells [23,32]. Previous study has identi ed a potential therapeutic bene t of blocking EGFR with ge tinib in basal-like subtypes of TNBC in vitro [21]).…”

Section: Discussionmentioning

confidence: 99%

“…Lipid ROS increases after suppression of GPX4 [32]. Elimination of ROS sensitizes the BC cells to ge tinib [41].…”

Section: Discussionmentioning

confidence: 99%

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

Song

Wang

Liu

et al. 2020

Preprint

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Background: Gefitinib exhibits antitumor activity in the patients with breast cancer, but the resistance to gefitinib in triple negative breast cancer (TNBC) is a new concern. Glutathione peroxidase 4 (GPX4) is a leading regulator of ferroptosis, which is of importance for the survival of TNBC cells. This study investigated GPX4-mediated ferroptosis in gefitinib sensitivity in TNBC.Methods: Gefitinib resistant TNBC cells MDA-MB-231/Gef and HS578T/Gef were constructed, and treated with lentivirus sh-GPX4 and ferroptosis inhibitor ferrostatin-1. GPX4 expression, cell viability and apoptosis were detected. Malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS) levels were evaluated. The levels of ferroptosis-related proteins ACSL4, PTGS2, NOX1 and FTH1 were detected. Subcutaneous tumor model was established in nude mice, and gefitinib was intraperitoneally injected. Apoptosis was detected by TUNEL staining and Ki-67 expression was detected by immunohistochemistry.Results: GPX4 was increased in gefitinib-resistant cells. After silencing GPX4, the inhibition rate of cell viability increased, the limitation of colony formation ability reduced, apoptosis rate increased, and the sensitivity of cells to gefitinib was improved. After silencing GPX4, MDA level and ROS production were significantly increased, while GSH level was decreased. Silencing GPX4 promoted ferroptosis. After inhibition of ferroptosis by ferrostatin-1, it revealed that inhibition of GPX4 promoted gefitinib sensitivity by promoting cell ferroptosis. In vivo experiments also showed that inhibition of GPX4 enhanced the anticancer effect of gefitinib through promoting ferroptosis.Conclusion: Inhibition of GPX4 stimulated ferroptosis and thus enhanced TNBC cell sensitivity to gefitinib.

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Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine

Cited by 217 publications

References 38 publications

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

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