The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer
Abstract Background Ferroptosis-induced therapy is a promising approach for treating anaplastic thyroid carcinoma (ATC), a highly lethal form of cancer. However, the specific effects of two anti-angiogenic agents, lenvatinib and anlotinib, on ferroptosis in ATC are not well understood. Methods Metho...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
|
| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12935-025-03947-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849225896758607872 |
|---|---|
| author | Yehao Guo Juyong Liang Lingling Ding Jiajun Wu Weidong Teng Jiafeng Wang Liehao Jiang Zhuo Tan |
| author_facet | Yehao Guo Juyong Liang Lingling Ding Jiajun Wu Weidong Teng Jiafeng Wang Liehao Jiang Zhuo Tan |
| author_sort | Yehao Guo |
| collection | DOAJ |
| description | Abstract Background Ferroptosis-induced therapy is a promising approach for treating anaplastic thyroid carcinoma (ATC), a highly lethal form of cancer. However, the specific effects of two anti-angiogenic agents, lenvatinib and anlotinib, on ferroptosis in ATC are not well understood. Methods Methods: To investigate the anticancer activity of lenvatinib and anlotinib in vivo, a subcutaneous tumor model was established in mice. The pharmacological effects of these agents on ATC cells were assessed using various assays, including CCK-8, colony formation, transwell, and sphere-forming assays. Angiogenesis was evaluated using a tubule formation assay. Reactive oxygen species (ROS) levels were measured by flow cytometry, and levels of ferroptosis and endoplasmic reticulum (ER) stress were determined through western blot assays. Immunohistochemistry analyses were used to profile the expression of GPX4, HO-1, PERK, and CHOP in tumor tissues. Results Both lenvatinib and anlotinib demonstrated dose- and time-dependent inhibition of Luciferase-8505 C-induced subcutaneous tumors in mice, with anlotinib showing greater efficacy than lenvatinib. In vitro experiments revealed that while both drugs were effective at inhibiting angiogenesis, anlotinib displayed superior antitumor effects in terms of cell viability, proliferation, tumor sphere formation, migration, and invasion. Mechanistic studies indicated that anlotinib induced ROS-mediated ferroptosis through the ER stress pathway, a response not observed with lenvatinib treatment. Conclusion Anlotinib showed superior efficacy in treating ATC compared to lenvatinib, independent of their anti-angiogenic properties. The ability of anlotinib to induce ER stress-mediated ferroptosis suggests that targeting ferroptosis may hold promise as a therapeutic strategy for ATC. Graphical Abstract |
| format | Article |
| id | doaj-art-2aae0fe7cb3045cc9b5dc894e6d3c537 |
| institution | Kabale University |
| issn | 1475-2867 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj-art-2aae0fe7cb3045cc9b5dc894e6d3c5372025-08-24T11:51:28ZengBMCCancer Cell International1475-28672025-08-0125111510.1186/s12935-025-03947-zThe endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancerYehao Guo0Juyong Liang1Lingling Ding2Jiajun Wu3Weidong Teng4Jiafeng Wang5Liehao Jiang6Zhuo Tan7Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical CollegeOtolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical CollegeOtolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical CollegeZhejiang Provincial Clinical Research Center for Head & Neck CancerOtolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical CollegeOtolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical CollegeOtolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical CollegeOtolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical CollegeAbstract Background Ferroptosis-induced therapy is a promising approach for treating anaplastic thyroid carcinoma (ATC), a highly lethal form of cancer. However, the specific effects of two anti-angiogenic agents, lenvatinib and anlotinib, on ferroptosis in ATC are not well understood. Methods Methods: To investigate the anticancer activity of lenvatinib and anlotinib in vivo, a subcutaneous tumor model was established in mice. The pharmacological effects of these agents on ATC cells were assessed using various assays, including CCK-8, colony formation, transwell, and sphere-forming assays. Angiogenesis was evaluated using a tubule formation assay. Reactive oxygen species (ROS) levels were measured by flow cytometry, and levels of ferroptosis and endoplasmic reticulum (ER) stress were determined through western blot assays. Immunohistochemistry analyses were used to profile the expression of GPX4, HO-1, PERK, and CHOP in tumor tissues. Results Both lenvatinib and anlotinib demonstrated dose- and time-dependent inhibition of Luciferase-8505 C-induced subcutaneous tumors in mice, with anlotinib showing greater efficacy than lenvatinib. In vitro experiments revealed that while both drugs were effective at inhibiting angiogenesis, anlotinib displayed superior antitumor effects in terms of cell viability, proliferation, tumor sphere formation, migration, and invasion. Mechanistic studies indicated that anlotinib induced ROS-mediated ferroptosis through the ER stress pathway, a response not observed with lenvatinib treatment. Conclusion Anlotinib showed superior efficacy in treating ATC compared to lenvatinib, independent of their anti-angiogenic properties. The ability of anlotinib to induce ER stress-mediated ferroptosis suggests that targeting ferroptosis may hold promise as a therapeutic strategy for ATC. Graphical Abstracthttps://doi.org/10.1186/s12935-025-03947-zAnlotinibLenvatinibFerroptosisEndoplasmic reticulum stressAnaplastic thyroid cancerSignal pathways. |
| spellingShingle | Yehao Guo Juyong Liang Lingling Ding Jiajun Wu Weidong Teng Jiafeng Wang Liehao Jiang Zhuo Tan The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer Cancer Cell International Anlotinib Lenvatinib Ferroptosis Endoplasmic reticulum stress Anaplastic thyroid cancer Signal pathways. |
| title | The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer |
| title_full | The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer |
| title_fullStr | The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer |
| title_full_unstemmed | The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer |
| title_short | The endoplasmic reticulum stress-ferroptosis reciprocal signaling orchestrates anti-tumor effect of anlotinib in anaplastic thyroid cancer |
| title_sort | endoplasmic reticulum stress ferroptosis reciprocal signaling orchestrates anti tumor effect of anlotinib in anaplastic thyroid cancer |
| topic | Anlotinib Lenvatinib Ferroptosis Endoplasmic reticulum stress Anaplastic thyroid cancer Signal pathways. |
| url | https://doi.org/10.1186/s12935-025-03947-z |
| work_keys_str_mv | AT yehaoguo theendoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT juyongliang theendoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT linglingding theendoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT jiajunwu theendoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT weidongteng theendoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT jiafengwang theendoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT liehaojiang theendoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT zhuotan theendoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT yehaoguo endoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT juyongliang endoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT linglingding endoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT jiajunwu endoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT weidongteng endoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT jiafengwang endoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT liehaojiang endoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer AT zhuotan endoplasmicreticulumstressferroptosisreciprocalsignalingorchestratesantitumoreffectofanlotinibinanaplasticthyroidcancer |