The suppression of cervical cancer ferroptosis by macrophages: The attenuation of ALOX15 in cancer cells by macrophages-derived exosomes

Yanlin Luo; Yibing Chen; Huan Jin; Benxin Hou; Hongsheng Li; Xiang Li; Lingfeng Liu; Yuan Zhou; Yonghua Li; Yong Sang Song; Quentin Liu; Zhengzhi Zou

doi:10.1016/j.apsb.2023.03.025

The suppression of cervical cancer ferroptosis by macrophages: The attenuation of ALOX15 in cancer cells by macrophages-derived exosomes

Acta Pharm Sin B. 2023 Jun;13(6):2645-2662. doi: 10.1016/j.apsb.2023.03.025. Epub 2023 Mar 31.

Authors

Yanlin Luo^{1

2

3}, Yibing Chen⁴, Huan Jin², Benxin Hou⁵, Hongsheng Li⁶, Xiang Li⁷, Lingfeng Liu², Yuan Zhou², Yonghua Li², Yong Sang Song⁸, Quentin Liu⁹, Zhengzhi Zou^{2

10}

Affiliations

¹ Department of Gynecologic Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450001, China.
² MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
³ Institute of Clinical Pharmacology, School of Basic Medical Science, Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, China.
⁴ Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450001, China.
⁵ Department of General Surgery, the Third People's Hospital of Hainan Province, Sanya 572000, China.
⁶ Department of Breast Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.
⁷ Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
⁸ Department of Obstetrics and Gynecology, Cancer Research Institute, College of Medicine, Seoul National University, Seoul 03080, South Korea.
⁹ State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510631, China.
¹⁰ Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, China.

Abstract

Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types. Tumor-associated macrophages (TAMs) play a key role in promoting tumor malignant progression and therapy resistance. However, the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic. This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo. TAMs have been found to suppress cervical cancer cells ferroptosis. Mechanistically, macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells. In cancer cells, miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis. Moreover, the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway. Importantly, in clinical cervical cancer cases, ALOX15 is negatively associated with macrophages infiltration, which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer. Moreover, both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer. Altogether, this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.

Keywords: ALOX15; Cervical cancer; Exosome; Ferroptosis; Macrophages infiltration; STAT6; Tumor-associated macrophage; miRNA-660-5p.