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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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/16/9014 |
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| author | Shujie Liu Shuai Yan Jie Zhu Ruiqing Lu Chujie Kang Kang Tang Jinfeng Zeng Mingmei Ding Zixiang Guo Xianxin Lai Yinan Jiang Siqing Wu Lihua Zhou Litao Sun Zhong-Wei Zhou |
| author_facet | Shujie Liu Shuai Yan Jie Zhu Ruiqing Lu Chujie Kang Kang Tang Jinfeng Zeng Mingmei Ding Zixiang Guo Xianxin Lai Yinan Jiang Siqing Wu Lihua Zhou Litao Sun Zhong-Wei Zhou |
| author_sort | Shujie Liu |
| collection | DOAJ |
| 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 <i>KRAS</i> and ferritin heavy chain (<i>FTH1</i>) since a high level of <i>FTH1</i> is associated with the poor prognostic survival of HNSCCs, but knocked down <i>FTH1</i> can promote HNSCC cell death. Excitingly, the ferroptosis-inducer RSL3 plays a synthetic role with EGFR monoclonal antibody <i>Cetuximab</i> 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 <i>FTH1</i> and a low level of <i>EGFR</i>, respectively. Our findings prove that <i>FTH1</i> plays a vital role in ferroptosis resistance in HNSCCs and also provide clues to target HNSCCs resistant to ferroptosis induction and/or EGFR inhibition. |
| first_indexed | 2024-03-09T09:56:11Z |
| format | Article |
| id | doaj.art-363e1cb0fc1e492cbe3d5fe875ac3a82 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T09:56:11Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-363e1cb0fc1e492cbe3d5fe875ac3a822023-12-01T23:47:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012316901410.3390/ijms23169014Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to CetuximabShujie Liu0Shuai Yan1Jie Zhu2Ruiqing Lu3Chujie Kang4Kang Tang5Jinfeng Zeng6Mingmei Ding7Zixiang Guo8Xianxin Lai9Yinan Jiang10Siqing Wu11Lihua Zhou12Litao Sun13Zhong-Wei Zhou14School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, ChinaHead 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 <i>KRAS</i> and ferritin heavy chain (<i>FTH1</i>) since a high level of <i>FTH1</i> is associated with the poor prognostic survival of HNSCCs, but knocked down <i>FTH1</i> can promote HNSCC cell death. Excitingly, the ferroptosis-inducer RSL3 plays a synthetic role with EGFR monoclonal antibody <i>Cetuximab</i> 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 <i>FTH1</i> and a low level of <i>EGFR</i>, respectively. Our findings prove that <i>FTH1</i> plays a vital role in ferroptosis resistance in HNSCCs and also provide clues to target HNSCCs resistant to ferroptosis induction and/or EGFR inhibition.https://www.mdpi.com/1422-0067/23/16/9014head and neck squamous cell carcinomasferroptosis<i>FTH1</i>cetuximab resistance |
| spellingShingle | Shujie Liu Shuai Yan Jie Zhu Ruiqing Lu Chujie Kang Kang Tang Jinfeng Zeng Mingmei Ding Zixiang Guo Xianxin Lai Yinan Jiang Siqing Wu Lihua Zhou Litao Sun Zhong-Wei Zhou Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab International Journal of Molecular Sciences head and neck squamous cell carcinomas ferroptosis <i>FTH1</i> cetuximab resistance |
| 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 | head and neck squamous cell carcinomas ferroptosis <i>FTH1</i> cetuximab resistance |
| url | https://www.mdpi.com/1422-0067/23/16/9014 |
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