Home Neoplasma 2022 Neoplasma Vol.69, No.5, p.1054–1069, 2022

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Neoplasma Vol.69, No.5, p.1054–1069, 2022

Title: HSPA5 repressed ferroptosis to promote colorectal cancer development by maintaining GPX4 stability
Author: Ronglin Wang, Lei Hua, Peixiang Ma, Yang Song, Jie Min, Yongdong Guo, Cheng Yang, Junqiang Li, Haichuan Su

Abstract: Colorectal cancer (CRC) is one of the most malignant cancers and its pathological mechanism is largely unknown. Unfolded protein response and ferroptosis are both critical factors involved in CRC development. However, their relationship in CRC remains to be explored. In this study, erastin was used to induce ferroptosis in CRC cells. Ferroptosis was confirmed by the detection of glutathione, malondialdehyde, and lipid reactive oxygen species. The CRC datasets were analyzed using the R software, GEPIA2 and TIMER2.0. The results indicated that GPX4 was decreased when treated with the ferroptosis inducer erastin. As an intrinsic protective pathway, the unfolded protein response was activated and HSPA5 was increased during ferroptosis. HSPA5 was found to attenuate erastin-induced GPX4 decrease, repress ferroptosis, and promote CRC cell growth both in vitro and in vivo. Mechanistically, HSPA5 bound directly to GPX4 and the interaction between HSPA5 and GPX4 increased when treated with erastin for a short time period. Although the HSPA5-GPX4 interaction failed to completely reverse erastin-induced GPX4 decrease, HSPA5 slowed down GPX4 degradation process and gave CRC cells more time to adjust to erastin toxicity. Additionally, HSPA5 was demonstrated to play a diagnostic role and correlated to immune microenvironment in CRC patients. Our study demonstrates that increased HSPA5 was an intrinsic protective strategy to resist ferroptosis. Specifically, HSPA5 restrained ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. Our study provides potential diagnostic and therapeutic targets for patients with CRC.

Keywords: colorectal cancer; unfolded protein response; HSPA5; ferroptosis; GPX4
Published online: 20-Jun-2022
Year: 2022, Volume: 69, Issue: 5 Page From: 1054, Page To: 1069
Price: 33.60 €

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