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Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab

Head and neck squamous cell carcinomas (HNSCCs) are a type of cancer originating in the mucosal epithelium of the mouth, pharynx, and larynx, the sixth most common cancer in the world. However, there is no effective treatment for HNSCCs. More than 90% of HNSCCs overexpress epidermal growth factor re...

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Autores principales: Liu, Shujie, Yan, Shuai, Zhu, Jie, Lu, Ruiqing, Kang, Chujie, Tang, Kang, Zeng, Jinfeng, Ding, Mingmei, Guo, Zixiang, Lai, Xianxin, Jiang, Yinan, Wu, Siqing, Zhou, Lihua, Sun, Litao, Zhou, Zhong-Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409433/
https://www.ncbi.nlm.nih.gov/pubmed/36012290
http://dx.doi.org/10.3390/ijms23169014
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author Liu, Shujie
Yan, Shuai
Zhu, Jie
Lu, Ruiqing
Kang, Chujie
Tang, Kang
Zeng, Jinfeng
Ding, Mingmei
Guo, Zixiang
Lai, Xianxin
Jiang, Yinan
Wu, Siqing
Zhou, Lihua
Sun, Litao
Zhou, Zhong-Wei
author_facet Liu, Shujie
Yan, Shuai
Zhu, Jie
Lu, Ruiqing
Kang, Chujie
Tang, Kang
Zeng, Jinfeng
Ding, Mingmei
Guo, Zixiang
Lai, Xianxin
Jiang, Yinan
Wu, Siqing
Zhou, Lihua
Sun, Litao
Zhou, Zhong-Wei
author_sort Liu, Shujie
collection PubMed
description Head and neck squamous cell carcinomas (HNSCCs) are a type of cancer originating in the mucosal epithelium of the mouth, pharynx, and larynx, the sixth most common cancer in the world. However, there is no effective treatment for HNSCCs. More than 90% of HNSCCs overexpress epidermal growth factor receptors (EGFRs). Although small molecule inhibitors and monoclonal antibodies have been developed to target EGFRs, few EGFR-targeted therapeutics are approved for clinical use. Ferroptosis is a new kind of programmed death induced by the iron catalyzed excessive peroxidation of polyunsaturated fatty acids. A growing body of evidence suggests that ferroptosis plays a pivotal role in inhibiting the tumor process. However, whether and how ferroptosis-inducers (FINs) play roles in hindering HNSCCs are unclear. In this study, we analyzed the sensitivity of different HNSCCs to ferroptosis-inducers. We found that only tongue squamous cell carcinoma cells and laryngeal squamous cell carcinoma cells, but not nasopharyngeal carcinoma cells, actively respond to ferroptosis-inducers. The different sensitivities of HNSCC cells to ferroptosis induction may be attributed to the expression of KRAS and ferritin heavy chain (FTH1) since a high level of FTH1 is associated with the poor prognostic survival of HNSCCs, but knocked down FTH1 can promote HNSCC cell death. Excitingly, the ferroptosis-inducer RSL3 plays a synthetic role with EGFR monoclonal antibody Cetuximab to inhibit the survival of nasopharyngeal carcinoma cells (CNE-2), which are insensitive to both ferroptosis induction and EGFR inhibition due to a high level of FTH1 and a low level of EGFR, respectively. Our findings prove that FTH1 plays a vital role in ferroptosis resistance in HNSCCs and also provide clues to target HNSCCs resistant to ferroptosis induction and/or EGFR inhibition.
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spelling pubmed-94094332022-08-26 Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab Liu, Shujie Yan, Shuai Zhu, Jie Lu, Ruiqing Kang, Chujie Tang, Kang Zeng, Jinfeng Ding, Mingmei Guo, Zixiang Lai, Xianxin Jiang, Yinan Wu, Siqing Zhou, Lihua Sun, Litao Zhou, Zhong-Wei Int J Mol Sci Article Head and neck squamous cell carcinomas (HNSCCs) are a type of cancer originating in the mucosal epithelium of the mouth, pharynx, and larynx, the sixth most common cancer in the world. However, there is no effective treatment for HNSCCs. More than 90% of HNSCCs overexpress epidermal growth factor receptors (EGFRs). Although small molecule inhibitors and monoclonal antibodies have been developed to target EGFRs, few EGFR-targeted therapeutics are approved for clinical use. Ferroptosis is a new kind of programmed death induced by the iron catalyzed excessive peroxidation of polyunsaturated fatty acids. A growing body of evidence suggests that ferroptosis plays a pivotal role in inhibiting the tumor process. However, whether and how ferroptosis-inducers (FINs) play roles in hindering HNSCCs are unclear. In this study, we analyzed the sensitivity of different HNSCCs to ferroptosis-inducers. We found that only tongue squamous cell carcinoma cells and laryngeal squamous cell carcinoma cells, but not nasopharyngeal carcinoma cells, actively respond to ferroptosis-inducers. The different sensitivities of HNSCC cells to ferroptosis induction may be attributed to the expression of KRAS and ferritin heavy chain (FTH1) since a high level of FTH1 is associated with the poor prognostic survival of HNSCCs, but knocked down FTH1 can promote HNSCC cell death. Excitingly, the ferroptosis-inducer RSL3 plays a synthetic role with EGFR monoclonal antibody Cetuximab to inhibit the survival of nasopharyngeal carcinoma cells (CNE-2), which are insensitive to both ferroptosis induction and EGFR inhibition due to a high level of FTH1 and a low level of EGFR, respectively. Our findings prove that FTH1 plays a vital role in ferroptosis resistance in HNSCCs and also provide clues to target HNSCCs resistant to ferroptosis induction and/or EGFR inhibition. MDPI 2022-08-12 /pmc/articles/PMC9409433/ /pubmed/36012290 http://dx.doi.org/10.3390/ijms23169014 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Shujie
Yan, Shuai
Zhu, Jie
Lu, Ruiqing
Kang, Chujie
Tang, Kang
Zeng, Jinfeng
Ding, Mingmei
Guo, Zixiang
Lai, Xianxin
Jiang, Yinan
Wu, Siqing
Zhou, Lihua
Sun, Litao
Zhou, Zhong-Wei
Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab
title Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab
title_full Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab
title_fullStr Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab
title_full_unstemmed Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab
title_short Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab
title_sort combination rsl3 treatment sensitizes ferroptosis- and egfr-inhibition-resistant hnsccs to cetuximab
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409433/
https://www.ncbi.nlm.nih.gov/pubmed/36012290
http://dx.doi.org/10.3390/ijms23169014
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