The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells

Louandre, Christophe; Marcq, Ingrid; Bouhlal, Hicham; Lachaier, Emma; Godin, C.; Saidak, Zuzana; François, Clément; Chatelain, Denis; Debuysscher, Véronique; Barbare, Jean‐Claude; Chauffert, Bruno; Galmiche, Antoine

doi:10.1016/j.canlet.2014.11.014

Cited by 315 publications

(242 citation statements)

References 26 publications

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“…The adverse event profile of sorafenib in patients was found to be consistent with the notion that sorafenib exerts additional activity in vivo compared to other similar kinase inhibiting drugs that do not inhibit system x c − [29]. Recently, the retinoblastoma protein (Rb) was found to suppress ferroptosis in response to sorafenib [30], suggesting that Rb status may aid in selecting ferroptosis-sensitive tumors, at least for sorafenib.…”

Section: Emerging Ferroptosis-inducing Compounds and Mechanismsmentioning

confidence: 57%

Ferroptosis: Death by Lipid Peroxidation

Yang

Stockwell

2016

Trends in Cell Biology

1,938

1,468

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Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid-based reactive oxygen species, particularly lipid hydroperoxides. This form of iron-dependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis, unregulated necrosis, and necroptosis. Ferroptosis is regulated by specific pathways and is involved in diverse biological contexts. Here, we summarize the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology.

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Section: Emerging Ferroptosis-inducing Compounds and Mechanismsmentioning

confidence: 57%

Ferroptosis: Death by Lipid Peroxidation

Yang

Stockwell

2016

Trends in Cell Biology

1,938

1,468

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“…At present, the only clinically-approved inducer of ferroptosis is the Raf kinase inhibitor sorafenib [57, 58], whose effectiveness in ferroptosis induction is limited by specific concentration ranges [30]. ART is well tolerated in malaria patients and pharmacokinetics have been characterized [15, 16].…”

Section: Discussionmentioning

confidence: 99%

Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells

et al. 2015

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Oncogenic KRas reprograms pancreatic ductal adenocarcinoma (PDAC) cells to states which are highly resistant to apoptosis. Thus, a major preclinical goal is to identify effective strategies for killing PDAC cells. Artesunate (ART) is an anti-malarial that specifically induces programmed cell death in different cancer cell types, in a manner initiated by reactive oxygen species (ROS)-generation. In this study we demonstrate that ART specifically induced ROS- and lysosomal iron-dependent cell death in PDAC cell lines. Highest cytotoxicity was obtained in PDAC cell lines with constitutively-active KRas, and ART did not affect non-neoplastic human pancreatic ductal epithelial (HPDE) cells. We determined that ART did not induce apoptosis or necroptosis. Instead, ART induced ferroptosis, a recently described mode of ROS- and iron-dependent programmed necrosis which can be activated in Ras-transformed cells. Co-treatment with the ferroptosis inhibitor ferrostatin-1 blocked ART-induced lipid peroxidation and cell death, and increased long-term cell survival and proliferation. Importantly, analysis of PDAC patient mRNA expression indicates a dependency on antioxidant homeostasis and increased sensitivity to free intracellular iron, both of which correlate with Ras-driven sensitivity to ferroptosis. Overall, our findings suggest that ART activation of ferroptosis is an effective, novel pathway for killing PDAC cells.

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“…Sorafenib induces ferroptosis in certain cancer cells such as hepatocellular carcinoma (HCC) cells. 14,15 Sorafenib-induced ferroptosis occurs independent from the oncogenic status of Ras, RAF, PIK3CA, and p53. 16 However, the expression of Rb (the prototype tumor suppressor gene) and NRF2 could inhibit sorafenib-induced ferroptosis in HCC.…”

Section: Morphologymentioning

confidence: 99%

“…16 However, the expression of Rb (the prototype tumor suppressor gene) and NRF2 could inhibit sorafenib-induced ferroptosis in HCC. 14,17 The mechanism and action of sorafenib in ferroptosis may depend on the inhibition of system X c − function, but not on GPX4 activity (Figure 1a). 7 This process is associated with upregulated ER stress.…”

Section: Morphologymentioning

confidence: 99%

Ferroptosis: process and function

et al. 2016

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Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. 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. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.

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The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells

Cited by 315 publications

References 26 publications

Ferroptosis: Death by Lipid Peroxidation

Ferroptosis: Death by Lipid Peroxidation

Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells

Ferroptosis: process and function

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