Melatonin increases Olaparib sensitivity and suppresses cancer-associated fibroblast infiltration via suppressing the LAMB3-CXCL2 axis in TNBC

Yi-Wen Lai; Zei-Wei Liu; Mei-Hsiang Lin; Ching-Chieh Yang; Cheng-Ying Chu; Chu-Hung Chung; Cheng-Wei Lin

doi:10.1016/j.phrs.2024.107429

Melatonin increases Olaparib sensitivity and suppresses cancer-associated fibroblast infiltration via suppressing the LAMB3-CXCL2 axis in TNBC

Pharmacol Res. 2024 Sep 19:209:107429. doi: 10.1016/j.phrs.2024.107429. Online ahead of print.

Authors

Yi-Wen Lai¹, Zei-Wei Liu², Mei-Hsiang Lin³, Ching-Chieh Yang⁴, Cheng-Ying Chu⁵, Chu-Hung Chung¹, Cheng-Wei Lin⁶

Affiliations

¹ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
² Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
³ School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
⁴ Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan; Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan; School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan.
⁵ CRISPR Gene Targeting Core Lab, Taipei Medical University, Taipei, Taiwan.
⁶ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: cwlin@tmu.edu.tw.

PMID: 39306019
DOI: 10.1016/j.phrs.2024.107429

Abstract

Triple-negative breast cancer (TNBC) is the most malignant breast cancer subtype, characterized with high aggressiveness and a high recurrence rate. Olaparib is the first US Food and Drug Administration-approved poly(ADP ribose) polymerase (PARP) inhibitor (PARPi) to treat breast cancer patients with a germline BRCA1 or BRCA2 mutation. However, resistance to Olaparib treatment restricts the therapeutic effects, and thus novel therapeutics are urgently required. In the present study, we identified that the combination of melatonin and Olaparib synergistically enhanced the sensitivity of TNBC cells. Moreover, melatonin exerted promising antitumor activities in Olaparib-resistant cells, implying the potential for its clinical application. An RNA-sequencing analysis revealed that melatonin treatment downregulated laminin subunit beta 3 (LAMB3) expression. Genetic ablation of LAMB3 significantly increased Olaparib sensitivity, and subsequently suppressed proliferation, epithelial-to-mesenchymal transition (EMT)-related gene expressions, and aggressiveness of breast cancer cells. Accordingly, LAMB3 expression was positively correlated with C-X-C motif chemokine ligand 2 (CXCL2), and they collaboratively promoted cancer-associated fibroblast (CAF) infiltration. An in vivo study demonstrated that combined treatment with melatonin and Olaparib showed enhanced inhibitory efficacy against tumor growth, LAMB3 expression, CXCL2 levels, and CAF infiltration compared to single treatment groups, and combined treatment with melatonin and Olaparib significantly ameliorated the immunosuppressive tumor microenvironment. These findings illustrate a promising therapeutic strategy using melatonin to overcome Olaparib resistance and activate antitumor immunity via attenuating the LAMB3-CXCL2 axis in breast cancer patients.

Keywords: CXCL2; Cancer-associated fibroblasts; Immune microenvironment; LAMB3; Melatonin; Olaparib; Triple-negative breast cancer.