Erastin Disrupts Mitochondrial Permeability Transition Pore (mPTP) and Induces Apoptotic Death of Colorectal Cancer Cells

Huo, Haizhong; Zhou, Zhiyuan; Qin, Jian; Liu, Wenyong; Wang, Bing; Gu, Yu

doi:10.1371/journal.pone.0154605

Cited by 87 publications

(54 citation statements)

References 32 publications

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“…The direct binding of erastin to voltage-dependent anion-selective channel protein 2 (VDAC2) and 3 (VDAC3) is necessary to induce ferroptosis, which involves a unique constellation of morphological, biochemical and genetic features and is distinct from apoptosis, various forms of necrosis and autophagy (3). Erastin also exerts cytotoxic effects on several human cancer cell lines by inducing oxidative stress and caspase-9-dependent apoptotic death (4), indicating that erastin potentially induces ferroptotic and apoptotic cell death.…”

Section: Introductionmentioning

confidence: 99%

Upregulation and activation of p53 by erastin‑induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells

et al. 2018

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The tumour‑suppressor protein p53 is a key regulator of multiple cellular processes and exerts its tumour‑suppressor function by inducing apoptotic cell death. However, emerging evidence indicates that p53 is also involved in inducing ferroptosis, which is a unique iron‑dependent form of non‑apoptotic cell death triggered by the RAS‑selective lethal small molecule erastin. Previous studies have shown that erastin exposure induces increased ROS accumulation and oxidative stress. In the present study, we incubated A549 cells with erastin and detected ROS accumulation. Semi‑quantitative western blotting was performed to analyse the effect of the induced ROS on p53 activity. To determine how ROS activate p53, NAC, an ROS scavenger, and KU‑55933, an ATM kinase inhibitor, were employed to co‑incubate with erastin, followed by western blot analysis. Either p53 or SLC7A11 siRNA was introduced into A549 cells to silence the target‑gene expression, followed by ROS detection to illustrate the regulatory role of ROS‑activated p53 on its target gene SLC7A11. Annexin V‑FITC/PI staining was performed to detect the induction of apoptotic cell death by erastin exposure. To further assess the effects of erastin treatment on cellular proliferation, EdU staining and cell cycle flow cytometric analysis were performed. Erastin exposure upregulated and activated p53 and thus, transcriptionally activated its downstream target genes, including p21 and Bax, in lung cancer A549 cells dependent on erastin‑induced ROS. Subsequently, activated p53 by erastin treatment suppressed SLC7A11 and induced ROS accumulation, indicating the potential feedback loop between p53 and erastin‑induced ROS. By employing the caspase inhibitor Z‑VAD‑FMK, it was revealed that erastin‑induced p53 contributed to both ferroptotic and apoptotic cell death and inhibited cell proliferation via arresting the cell cycle at G1 phase. Collectively, these results indicated that p53 may contribute to the cytotoxic and cytostatic effects associated with establishing a feedback loop with ROS induced by erastin.

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Section: Introductionmentioning

confidence: 99%

Upregulation and activation of p53 by erastin‑induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells

et al. 2018

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“…Erastin can also induce apoptosis in lung (e.g. A549) and colorectal cancer cell lines (e.g., HT-29, DLD-1, and Caco-2) via the activation of TP53 and mitochondrial oxidative injury [21,22]. More recently, the major pro-ferroptosis activity of erastin has been linked to directly blocking system x c − .…”

Section: The Discovery Of Ferroptosis and The Location Of Ferroptosismentioning

confidence: 99%

The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression

et al. 2020

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Ferroptosis, a novel form of regulated cell death, is different from other types of cell death in morphology, genetics and biochemistry. Increasing evidence indicates that ferroptosis has significant implications on cell death linked to cardiomyopathy, tumorigenesis, and cerebral hemorrhage to name a few. Here we summarize current literature on ferroptosis, including organelle dysfunction, signaling transduction pathways, metabolic reprogramming and epigenetic regulators in cancer progression. With regard to organelles, mitochondria-induced cysteine starvation, endoplasmic reticulum-related oxidative stress, lysosome dysfunction and golgi stress-related lipid peroxidation all contribute to induction of ferroptosis. Understanding the underlying mechanism in ferroptosis could provide insight into the treatment of various intractable diseases including cancers.

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“…While much of the ferroptotic death pathway identified thus far exists independently of the classical apoptotic pathway, initiation of ferroptosis appears to influence the activity or localization of select apoptotic proteins. Notably, the small molecular ferroptosis inducer, erastin, induced caspase-dependent apoptosis in colorectal cancer cell lines [154], perhaps due to mitochondrial translocation of the BH3 protein, BID [155]. HT-22 cells genetically disrupted for BID were resistant to erastin-induced cell death, maintained normal mitochondrial morphology and respiration, and reduced lipid peroxide formation [155].…”

Section: Crosstalk Between Apoptosis and Ferroptosismentioning

confidence: 99%

Double agents of cell death: novel emerging functions of apoptotic regulators

Lamb

2020

The FEBS Journal

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Apoptosis is a highly regulated form of cell death that is required for many homeostatic and pathological processes. Recently, alternative cell death pathways have emerged whose regulation is dependent on proteins with canonical functions in apoptosis. Dysregulation of apoptotic signaling frequently underlies the pathogenesis of many cancers, reinforcing the need to develop therapies that initiate alternative cell death processes. This review outlines the convergence points between apoptosis and other death pathways with the purpose of identifying novel strategies for the treatment of apoptosis-refractory cancers. Apoptosis proteins can play key roles in the initiation, regulation, and execution of nonapoptotic death processes that include necroptosis, autophagy, pyroptosis, mPTP-mediated necrosis, and ferroptosis. Notably, recent evidence illustrates that dying cells can exhibit biochemical and molecular characteristics of more than one different type of regulated cell death. Thus, this review highlights the amazing complexity and interconnectivity of cell death processes and also raises the idea that a top-to-bottom approach to describing cell death mechanisms may be inadequate for fully understanding the means by which cells die.

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Erastin Disrupts Mitochondrial Permeability Transition Pore (mPTP) and Induces Apoptotic Death of Colorectal Cancer Cells

Cited by 87 publications

References 32 publications

Upregulation and activation of p53 by erastin‑induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells

Upregulation and activation of p53 by erastin‑induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells

The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression

Double agents of cell death: novel emerging functions of apoptotic regulators

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