Cargando…

TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer

OBJECTIVE: Ferroptosis, a newly identified form of cell death, plays critical roles in the development and chemoresistance of lung cancer. Tripartite motif 6 (TRIM6) acts as an E3-ubiquitin ligase and can promote the progression of human colorectal cancer. The present study is aimed at investigating...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Ying, Dong, Ping, Liu, Nian, Yang, Jun-Yuan, Wang, Hui-Min, Geng, Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9842414/
https://www.ncbi.nlm.nih.gov/pubmed/36654781
http://dx.doi.org/10.1155/2023/9808100
_version_ 1784870120485552128
author Zhang, Ying
Dong, Ping
Liu, Nian
Yang, Jun-Yuan
Wang, Hui-Min
Geng, Qing
author_facet Zhang, Ying
Dong, Ping
Liu, Nian
Yang, Jun-Yuan
Wang, Hui-Min
Geng, Qing
author_sort Zhang, Ying
collection PubMed
description OBJECTIVE: Ferroptosis, a newly identified form of cell death, plays critical roles in the development and chemoresistance of lung cancer. Tripartite motif 6 (TRIM6) acts as an E3-ubiquitin ligase and can promote the progression of human colorectal cancer. The present study is aimed at investigating its role and potential mechanisms in lung cancer. METHODS: Lentiviral vectors were used to overexpress or knock down TRIM6 in human lung cancer cells. Cell survival, colony formation, lipid peroxidation, intracellular iron levels, and other ferroptotic markers were examined. The role of TRIM6 on ferroptosis and chemosensitivity was further tested in mouse tumor xenograft models. RESULTS: TRIM6 was highly expressed in human lung cancer tissues and cells, and its expression in the lung cancer cells was further increased by ferroptotic stimulation. TRIM6 overexpression inhibited, while TRIM6 silence promoted erastin- and RSL3-induced glutaminolysis and ferroptosis in the lung cancer cells. Mechanistically, TRIM6 directly interacted with solute carrier family 1 member 5 to promote its ubiquitination and degradation, thereby inhibiting glutamine import, glutaminolysis, lipid peroxidation, and ferroptotic cell death. Moreover, we observed that TRIM6 overexpression reduced the chemotherapeutic effects of cisplatin and paclitaxel. In contrast, TRIM6 silence sensitized human lung cancer cells to cisplatin and paclitaxel in vivo and in vitro. CONCLUSION: Our findings for the first time define TRIM6 as a negative regulator of ferroptosis in the lung cancer cells, and TRIM6 overexpression enhances the resistance of human lung cancer cells to chemotherapeutic drugs. Overall, targeting TRIM6 may help to establish novel strategies to treat lung cancer.
format Online
Article
Text
id pubmed-9842414
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Hindawi
record_format MEDLINE/PubMed
spelling pubmed-98424142023-01-17 TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer Zhang, Ying Dong, Ping Liu, Nian Yang, Jun-Yuan Wang, Hui-Min Geng, Qing Oxid Med Cell Longev Research Article OBJECTIVE: Ferroptosis, a newly identified form of cell death, plays critical roles in the development and chemoresistance of lung cancer. Tripartite motif 6 (TRIM6) acts as an E3-ubiquitin ligase and can promote the progression of human colorectal cancer. The present study is aimed at investigating its role and potential mechanisms in lung cancer. METHODS: Lentiviral vectors were used to overexpress or knock down TRIM6 in human lung cancer cells. Cell survival, colony formation, lipid peroxidation, intracellular iron levels, and other ferroptotic markers were examined. The role of TRIM6 on ferroptosis and chemosensitivity was further tested in mouse tumor xenograft models. RESULTS: TRIM6 was highly expressed in human lung cancer tissues and cells, and its expression in the lung cancer cells was further increased by ferroptotic stimulation. TRIM6 overexpression inhibited, while TRIM6 silence promoted erastin- and RSL3-induced glutaminolysis and ferroptosis in the lung cancer cells. Mechanistically, TRIM6 directly interacted with solute carrier family 1 member 5 to promote its ubiquitination and degradation, thereby inhibiting glutamine import, glutaminolysis, lipid peroxidation, and ferroptotic cell death. Moreover, we observed that TRIM6 overexpression reduced the chemotherapeutic effects of cisplatin and paclitaxel. In contrast, TRIM6 silence sensitized human lung cancer cells to cisplatin and paclitaxel in vivo and in vitro. CONCLUSION: Our findings for the first time define TRIM6 as a negative regulator of ferroptosis in the lung cancer cells, and TRIM6 overexpression enhances the resistance of human lung cancer cells to chemotherapeutic drugs. Overall, targeting TRIM6 may help to establish novel strategies to treat lung cancer. Hindawi 2023-01-09 /pmc/articles/PMC9842414/ /pubmed/36654781 http://dx.doi.org/10.1155/2023/9808100 Text en Copyright © 2023 Ying Zhang et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Zhang, Ying
Dong, Ping
Liu, Nian
Yang, Jun-Yuan
Wang, Hui-Min
Geng, Qing
TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer
title TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer
title_full TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer
title_fullStr TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer
title_full_unstemmed TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer
title_short TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer
title_sort trim6 reduces ferroptosis and chemosensitivity by targeting slc1a5 in lung cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9842414/
https://www.ncbi.nlm.nih.gov/pubmed/36654781
http://dx.doi.org/10.1155/2023/9808100
work_keys_str_mv AT zhangying trim6reducesferroptosisandchemosensitivitybytargetingslc1a5inlungcancer
AT dongping trim6reducesferroptosisandchemosensitivitybytargetingslc1a5inlungcancer
AT liunian trim6reducesferroptosisandchemosensitivitybytargetingslc1a5inlungcancer
AT yangjunyuan trim6reducesferroptosisandchemosensitivitybytargetingslc1a5inlungcancer
AT wanghuimin trim6reducesferroptosisandchemosensitivitybytargetingslc1a5inlungcancer
AT gengqing trim6reducesferroptosisandchemosensitivitybytargetingslc1a5inlungcancer