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Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer.
Free Radic Biol Med. 2018 12; 129:454-462.FR

Abstract

Glutathione peroxidase 4 (GPX4) is a regulator of ferroptosis (iron-dependent, non-apoptotic cell death); its inhibition can render therapy-resistant cancer cells susceptible to ferroptosis. However, some cancer cells develop mechanisms protective against ferroptosis; understanding these mechanisms could help overcome chemoresistance. In this study, we investigated the molecular mechanisms underlying resistance to ferroptosis induced by GPX4 inhibition in head and neck cancer (HNC). The effects of two GPX4 inhibitors, (1S, 3R)-RSL3 and ML-162, and of trigonelline were tested in HNC cell lines, including cisplatin-resistant (HN3R) and acquired RSL3-resistant (HN3-rslR) cells. The effects of the inhibitors and trigonelline, as well as of inhibition of the p62, Keap1, or Nrf2 genes, were assessed by cell viability, cell death, lipid ROS production, and protein expression, and in mouse tumor xenograft models. Treatment with RSL3 or ML-162 induced the ferroptosis of HNC cells to varying degrees. RSL3 or ML-162 treatment increased the expression of p62 and Nrf2 in chemoresistant HN3R and HN3-rslR cells, inactivated Keap1, and increased expression of the phospho-PERK-ATF4-SESN2 pathway. Transcriptional activation of Nrf2 was associated with resistance to ferroptosis. Overexpression of Nrf2 by inhibiting Keap1 or Nrf2 gene transfection rendered chemosensitive HN3 cells resistant to RSL3. However, Nrf2 inhibition or p62 silencing sensitized HN3R cells to RSL3. Trigonelline sensitized chemoresistant HNC cells to RSL3 treatment in a mouse model transplanted with HN3R. Thus, activation of the Nrf2-ARE pathway contributed to the resistance of HNC cells to GPX4 inhibition, and inhibition of this pathway reversed the resistance to ferroptosis in HNC.

Authors+Show Affiliations

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: rohjl@amc.seoul.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30339884

Citation

Shin, Daiha, et al. "Nrf2 Inhibition Reverses Resistance to GPX4 Inhibitor-induced Ferroptosis in Head and Neck Cancer." Free Radical Biology & Medicine, vol. 129, 2018, pp. 454-462.
Shin D, Kim EH, Lee J, et al. Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med. 2018;129:454-462.
Shin, D., Kim, E. H., Lee, J., & Roh, J. L. (2018). Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radical Biology & Medicine, 129, 454-462. https://doi.org/10.1016/j.freeradbiomed.2018.10.426
Shin D, et al. Nrf2 Inhibition Reverses Resistance to GPX4 Inhibitor-induced Ferroptosis in Head and Neck Cancer. Free Radic Biol Med. 2018;129:454-462. PubMed PMID: 30339884.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. AU - Shin,Daiha, AU - Kim,Eun Hye, AU - Lee,Jaewang, AU - Roh,Jong-Lyel, Y1 - 2018/10/16/ PY - 2018/04/08/received PY - 2018/09/15/revised PY - 2018/10/13/accepted PY - 2018/10/20/pubmed PY - 2019/9/29/medline PY - 2018/10/20/entrez KW - Ferroptosis KW - GPX4 KW - Head and neck cancer KW - Nrf2 KW - p62 SP - 454 EP - 462 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 129 N2 - Glutathione peroxidase 4 (GPX4) is a regulator of ferroptosis (iron-dependent, non-apoptotic cell death); its inhibition can render therapy-resistant cancer cells susceptible to ferroptosis. However, some cancer cells develop mechanisms protective against ferroptosis; understanding these mechanisms could help overcome chemoresistance. In this study, we investigated the molecular mechanisms underlying resistance to ferroptosis induced by GPX4 inhibition in head and neck cancer (HNC). The effects of two GPX4 inhibitors, (1S, 3R)-RSL3 and ML-162, and of trigonelline were tested in HNC cell lines, including cisplatin-resistant (HN3R) and acquired RSL3-resistant (HN3-rslR) cells. The effects of the inhibitors and trigonelline, as well as of inhibition of the p62, Keap1, or Nrf2 genes, were assessed by cell viability, cell death, lipid ROS production, and protein expression, and in mouse tumor xenograft models. Treatment with RSL3 or ML-162 induced the ferroptosis of HNC cells to varying degrees. RSL3 or ML-162 treatment increased the expression of p62 and Nrf2 in chemoresistant HN3R and HN3-rslR cells, inactivated Keap1, and increased expression of the phospho-PERK-ATF4-SESN2 pathway. Transcriptional activation of Nrf2 was associated with resistance to ferroptosis. Overexpression of Nrf2 by inhibiting Keap1 or Nrf2 gene transfection rendered chemosensitive HN3 cells resistant to RSL3. However, Nrf2 inhibition or p62 silencing sensitized HN3R cells to RSL3. Trigonelline sensitized chemoresistant HNC cells to RSL3 treatment in a mouse model transplanted with HN3R. Thus, activation of the Nrf2-ARE pathway contributed to the resistance of HNC cells to GPX4 inhibition, and inhibition of this pathway reversed the resistance to ferroptosis in HNC. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/30339884/Nrf2_inhibition_reverses_resistance_to_GPX4_inhibitor_induced_ferroptosis_in_head_and_neck_cancer_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(18)32219-6 DB - PRIME DP - Unbound Medicine ER -