HSPB1 as a Novel Regulator of Ferroptotic Cancer Cell Death

By Xiaofang Sun, Z. Ou, Min Xie, R. Kang, Yong Fan, X. Niu, Haichao Wang, Lizhi Cao, D. Tang. Oncogene, 2015

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Ferroptosis is an iron-dependent form of non-apoptotic cell death, but its molecular mechanism remains largely unknown. Here, we demonstrate that heat shock protein beta-1 (HSPB1) is a negative regulator of ferroptotic cancer cell death. Erastin, a specific ferroptosis-inducing compound, stimulates heat shock factor 1 (HSF1)-dependent HSPB1 expression in cancer cells. Knockdown of HSF1 and HSPB1 enhances erastin-induced ferroptosis, whereas heat shock pretreatment and overexpression of HSPB1 inhibits erastin-induced ferroptosis. Protein kinase C-mediated HSPB1 phosphorylation confers protection against ferroptosis by reducing iron-mediated production of lipid reactive oxygen species. Moreover, inhibition of the HSF1–HSPB1 pathway and HSPB1 phosphorylation increases the anticancer activity of erastin in human xenograft mouse tumor models. Our findings reveal an essential role for HSPB1 in iron metabolism with important effects on ferroptosis-mediated cancer therapy.

Subfields: Cell Biology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/a573591b84938eda977b2f521b7a755e0ef3419a

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Citations in the corpus

Metallothionein-1G Facilitates Sorafenib Resistance through Inhibition of Ferroptosis (2016, background): “For example, glutathione peroxidase 4((28)) and heat shock protein beta-1((42)) inhibit ferroptosis by limiting lipid peroxidation and reducing cellular iron uptake, respectively.”
Ferroptosis: Death by Lipid Peroxidation. (2016, background): “Finally, heat shock protein beta 1 (HSPB1) was reported to suppress ferroptosis through an unknown mechanism [41]; this suggests that heat shock proteins may be important in setting the sensitivity to ferroptosis in some cell contexts.”
The Tumor Suppressor Protein p53 and the Ferroptosis Network (2018, unknown): “Although the half-life of erastin is relatively short in vivo, it exhibits anticancer activity in multiple mouse models, indicating that yet-to-be-discovered metabolites produced from erastin may mediate antineoplastic effects [28,29].”
Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis (2022, background): “They are implicated in the regulation of iron uptake and subsequent lipid limits iron uptake in ferroptosis [51].”
Activation of the p62-Keap1-NRF2 Pathway Protects against Ferroptosis in Hepatocellular Carcinoma Cells (2015, background): “Heat shock protein beta1, a member of the molecular chaperones, can regulate actin filament dynamics and reduce cellular iron uptake in the induction of ferroptosis.(24) More recently, p53 was found to act as a positive regulator of ferroptosis by inhibiting expression of SLC7A11 (a specific light c”