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The role of heat shock protein beta-1 in erastin-induced ferroptosis

 

Ferroptosis is a kind of non-apoptotic cell death characterized by the overwhelming, iron-dependent accumulation of lethal lipid reactive oxygen species (ROS). Due to the lack of classic morphological and biochemical features of apoptosis and necrosis, molecular mechanism of the process remains largely unknown. Sun et al. found heat shock protein beta-1 (HSPB1) as a key negative mediator of ferroptotic cancer cell death. The article was published in Oncogene.  

                                                  

HSPs, regulated by the master transcriptional factors heat shock factors (HSFs), are expressed under normal conditions, but upregulated under stressful conditions, such as heat shock. They mainly function as molecular chaperones against harmful stimuli, and have been reported to prevent cancer cells from apoptosis and necrosis in both chaperone activity-dependent and -independent ways. In this study, researchers demonstrate that HSPB1, a member of small HSPs, is stimulated by erastin-induced ferroptosis in several types of cancer cells. The phosphorylation of HSPB1 negatively regulates ferroptosis by reducing cellular iron uptake, consequently leads to a reduction of lipid ROS production. This process is mediated by protein kinase C (PKC). On the other hand, knockdown of HSF1 and HSPB1 enhances ferroptosis induced by erastin. Strikingly, the inhibition of HSF1-HSPB1 signaling strengthens the anticancer activity of erastin in human exnograft mouse tumor models. These findings indicate that HSF1-HSPB1 signaling plays a key role in iron metabolism, and may act as a potential therapeutic target against ferroptosis-mediated cancer.

 

Reference:
Oncogene. 2015 Mar 2. doi: 10.1038/onc.2015.32.

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