Urolithin A inhibits breast cancer progression via activating TFEB-mediated mitophagy in tumor macrophages

Bowen Zheng; Yuying Wang; Baian Zhou; Fengyuan Qian; Diya Liu; Danrong Ye; Xiqian Zhou; Lin Fang

doi:10.1016/j.jare.2024.04.010

Urolithin A inhibits breast cancer progression via activating TFEB-mediated mitophagy in tumor macrophages

J Adv Res. 2024 Apr 12:S2090-1232(24)00153-X. doi: 10.1016/j.jare.2024.04.010. Online ahead of print.

Authors

Bowen Zheng¹, Yuying Wang¹, Baian Zhou¹, Fengyuan Qian¹, Diya Liu¹, Danrong Ye², Xiqian Zhou¹, Lin Fang³

Affiliations

¹ Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
² Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China.
³ Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China. Electronic address: fanglin2017@126.com.

PMID: 38615740
DOI: 10.1016/j.jare.2024.04.010

Abstract

Introduction: Urolithin A (UA) is a naturally occurring compound that is converted from ellagitannin-like precursors in pomegranates and nuts by intestinal flora. Previous studies have found that UA exerts tumor-suppressive effects through antitumor cell proliferation and promotion of memory T-cell expansion, but its role in tumor-associated macrophages remains unknown.

Objectives: Our study aims to reveal how UA affects tumor macrophages and tumor cells to inhibit breast cancer progression.

Methods: Observe the effect of UA treatment on breast cancer progression though in vivo and in vitro experiments. Western blot and PCR assays were performed to discover that UA affects tumor macrophage autophagy and inflammation. Co-ip and Molecular docking were used to explore specific molecular mechanisms.

Results: We observed that UA treatment could simultaneously inhibit harmful inflammatory factors, especially for InterleuKin-6 (IL-6) and tumor necrosis factor α (TNF-α), in both breast cancer cells and tumor-associated macrophages, thereby improving the tumor microenvironment and delaying tumor progression. Mechanistically, UA induced the key regulator of autophagy, transcription factor EB (TFEB), into the nucleus in a partially mTOR-dependent manner and inhibited the ubiquitination degradation of TFEB, which facilitated the clearance of damaged mitochondria via the mitophagy-lysosomal pathway in macrophages under tumor supernatant stress, and reduced the deleterious inflammatory factors induced by the release of nucleic acid from damaged mitochondria. Molecular docking and experimental studies suggest that UA block the recognition of TFEB by 1433 and induce TFEB nuclear localization. Notably, UA treatment demonstrated inhibitory effects on tumor progression in multiple breast cancer models.

Conclusion: Our study elucidated the anti-breast cancer effect of UA from the perspective of tumor-associated macrophages. Specifically, TFEB is a crucial downstream target in macrophages.

Keywords: Breast cancer; Mitophagy; TFEB; Tumor-associated macrophages; Urolithin A.