HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells

Zhu, Shan; Zhang, Qiuhong; Sun, Xiaofang; Zeh, Herbert J.; Lotze, Michael T.; Kang, Rui; Tang, Daolin

doi:10.1158/0008-5472.can-16-1979

Cited by 419 publications

(342 citation statements)

References 45 publications

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“…This erastin‐induced ATF4 elevation was inhibited when miR‐214 was forced to overexpress in these cancer cells. HSP5A, an anti‐ferroptosis molecule that is downstream to ATF4 (Zhu et al, 2017), showed similar expression patterns as ATF4 (Figure 3b–d). However, miR‐214 overexpression elevated the suppression of Nrf‐2 exposed to erastin (Figure 3c,d).…”

Section: Resultsmentioning

confidence: 62%

“…In human pancreatic ductal adenocarcinoma cells, HSPA5 prevented the degradation of GPX4, an antioxidant enzyme known to inhibit lipid peroxidation (Yang et al, 2014), thereby inhibiting ferroptosis (Zhu et al, 2017). Erastin upregulated HSPA5 mRNA and protein expression in a dose‐dependent manner, and ATF4 was responsible for this HSPA5 elevation (Zhu et al, 2017). In addition to inducing ATF4 downregulation, miR‐214 suppressed HSPA5 expression in hepatoma cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Bai

Liang

Zhu

et al. 2020

Journal Cellular Physiology

107

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Primary liver cancer is the second most frequent cause of cancer‐related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA‐214‐3p (miR‐214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR‐214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR‐214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre‐miR‐214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti‐miR‐214 sponge showed the opposite effect. Additionally, pre‐miR‐214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre‐miR‐214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR‐214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR‐214‐induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR‐214 elevated the ferroptosis‐promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis‐promoting effects of miR‐214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

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Section: Resultsmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Bai

Liang

Zhu

et al. 2020

Journal Cellular Physiology

107

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“…cDNA from various cell samples was amplified using real-time quantitative PCR with specific primers (Table S2). The data were normalized to 18S RNA and the fold change was calculated via the 2 −ΔΔCt method (Song et al, 2018; Zhu et al, 2017). Relative concentrations of mRNA were expressed in arbitrary units based on the untreated group, which was assigned a value of 1.…”

Section: Star Methodsmentioning

confidence: 99%

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Kang

Zeng

Zhu

et al. 2018

Cell Host & Microbe

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458

301

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Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage. The resultant N-terminal GSDMD fragments then trigger macrophage pyroptotic cell death in a phospholipase C gamma 1 (PLCG1)-dependent fashion. Administration of the antioxidant vitamin E that reduces lipid peroxidation, chemical inhibition of PLCG1, or genetic Caspase-11 deletion or Gsdmd inactivation prevents polymicrobial sepsis in Gpx4 mice. Collectively, this study suggests that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.

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“…As a key component of the unfolded protein response, HSPA5 promotes cell survival under conditions of endoplasmic reticulum stress-induced autophagy. A recent study demonstrated that upregulation of HSPA5 is a negative regulator of ferroptosis in pancreatic cancer cells [65]. Increased HSPA5 expression limits lipid peroxidation in ferroptosis by directly protecting against GPX4 degradation [65].…”

Section: Molecular Interactions Between Ferroptosis and Autophagymentioning

confidence: 99%

Autophagy and Ferroptosis—What Is the Connection?

2017

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Purpose of Review Autophagy is a conserved intracellular degradation system and plays a dual role in cell death, depending on context and phase. Ferroptosis is a new form of regulated cell death that mainly depends on iron accumulation and lipid peroxidation. In this review, we summarize the processes of autophagy and ferroptosis and discuss their crosstalk mechanisms at the molecular level. Recent Findings The original study shows that ferroptosis is morphologically, biochemically, and genetically distinct from autophagy and other types of cell death. However, recent studies demonstrate that activation of ferroptosis is indeed dependent on the induction of autophagy. Additionally, many ferroptosis regulators such as SLC7A11, GPX4, NRF2, p53, HSPB1, CISD1, FANCD2, and ACSL4 have been identified as potential regulators of autophagy. Summary This review not only highlights the importance of autophagy as an emerging mechanism of ferroptosis, but also raises new insights regarding regulated cell death.

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HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells

Cited by 419 publications

References 45 publications

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Autophagy and Ferroptosis—What Is the Connection?

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