Macroautophagy/autophagyis a lysosomal-regulated degradation process that participates incellular stress and then promotes cell survival or triggers celldeath. Ferroptosis was initially described as anautophagy-independent, iron-regulated, nonapoptotic cell death.However, recent studies have revealed that autophagy is positivelyassociated with sensitivity to ferroptosis. Nonetheless, themolecular mechanisms by which these two types of regulated cell death(RCD) modulate each other remain largely unclear. Here, we screened85 deubiquitinating enzymes (DUBs) and found that overexpression ofUSP13 (ubiquitin specific peptidase 13) could significantlyupregulate NFE2L2/NRF2 (NFE2 like bZIP transcription factor 2)protein levels. In addition, in 39 cases of KRAS-mutated lungadenocarcinoma (LUAD), we found that approximately 76% of USP13overexpression is positively correlated with NFE2L2 overexpression.USP13 interacts with and catalyzes the deubiquitination of thetranscription factor NFE2L2. Additionally, USP13 depletion promotesan autophagy-to-ferroptosis switch andin xenograft tumor mouse models, through the activation of theNFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 axis in KRAS mutant cellsand tumor tissues. Hence, targeting USP13 effectively switchedautophagy-to-ferroptosis, thereby inhibiting KRAS (KRASproto-oncogene, GTPase) mutant LUAD, suggesting the therapeuticpromise of combining autophagy and ferroptosis in the KRAS-mutantLUAD.
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http://dx.doi.org/10.1080/15548627.2024.2410619 | DOI Listing |
Autophagy
October 2024
Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Autophagy
December 2024
Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China.
Liver fibrosis is an invertible pathophysiologic process featured by excessive accumulation of extracellular matrix (ECM) which injures liver cells and activates hepatic stellate cells (HSCs). Besides, inducing ferroptosis in activated HSCs can alleviate liver fibrosis. LncRNAs modulate ferroptosis in activated HSCs and ECM deposition in liver fibrosis.
View Article and Find Full Text PDFFree Radic Biol Med
November 2023
Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea; Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea; Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea; Center for Nanomedicine, Institute for Basic Science (IBS), Yonsei University, Seoul, South Korea. Electronic address:
SQSTM1/p62 (sequestosome 1) is a multifunctional protein that serves as a receptor for selective autophagy and scaffold. In selective autophagy, p62 functions as a bridge between polyubiquitinated proteins and autophagosomes. Further, p62 acts as a signaling hub for many cellular pathways including mTORC1, NF-κB, and Keap1-Nrf2.
View Article and Find Full Text PDFInt J Biol Sci
May 2023
Department of Orthopedics, Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
Reprogramming metabolism is a hallmark of cancer cells for rapid progression. However, the detailed functional role of deubiquitinating enzymes (DUBs) in tumor glycolytic reprogramming is still unknown and requires further investigation. USP13 was found to upregulate in osteosarcoma (OS) specimens and promote OS progression through regulating aerobic glycolysis.
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