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Int J Biol Sci 2023; 19(8):2531-2550. doi:10.7150/ijbs.82120 This issue Cite

Research Paper

Anomanolide C suppresses tumor progression and metastasis by ubiquitinating GPX4-driven autophagy-dependent ferroptosis in triple negative breast cancer

Yan-Mei Chen^1,*, Wei Xu^3,*, Yang Liu^1,*, Jia-Hui Zhang^1,2, Yuan-Yuan Yang², Zhi-wen Wang², De-Juan Sun^1,✉, Hua Li^1,✉, Bo Liu^2,✉, Li-Xia Chen^1,✉

1. Wuya College of Innovation, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110000, China.
2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
3. Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Li-xia Chen, Wuya College of Innovation, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110000, China. E-mail: syzyclxcom; Bo Liu, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, No. 17, Renmin south Road, Sichuan University, Chengdu, 610041, China. E-mail: liubo2400com; Hua Li, Wuya College of Innovation, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110000, China. E-mail: li_huaedu.cn; De-juan Sun, Wuya College of Innovation, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110000, China. E-mail: 13693476164com. More

Abstract

Anomanolide C (AC), a natural withanolide isolated from Tubocapsicum anomalum, has been reported to have exhibits remarkable anti-tumour activities in several types of human cancers, particularly triple-negative breast cancer (TNBC). However, its intricate mechanisms still remain need to be clarified. Here, we evaluated whether AC could inhibit cell proliferation and the role of AC in ferroptosis induction and autophagy activation. Subsequently, the anti-migration potential of AC was found via autophagy-dependent ferroptosis. Additionally, we found that AC reduced the expression of GPX4 by ubiquitination and inhibited TNBC proliferation and metastasis in vitro and in vivo. Moreover, we demonstrated that AC induced autophagy-dependent ferroptosis, and led to Fe²⁺ accumulation via ubiquitinating GPX4. Moreover, AC was shown to induce autophagy-dependent ferroptosis as well as to inhibit TNBC proliferation and migration via GPX4 ubiquitination. Together, these results demonstrated that AC inhibited the progression and metastasis of TNBC by inducing autophagy-dependent ferroptosis via ubiquitinating GPX4, which might shed light on exploiting AC as a new drug candidate for the future TNBC therapy.

Keywords: Anomanolide C, Triple negative breast cancer, Autophagy, Ferroptosis, GPX4, Ubiquitination

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