Kaempferol Improves Breast Cancer-Related Depression through the COX-2/PGE2 Pathway

  • Front Biosci (Landmark Ed). 2023 Nov 28;28(11):311. doi: 10.31083/j.fbl2811311.
Qing Zhu  1 ,  Yuanshan Han  2 ,  Ying He  3 ,  Yilan Fu  1 ,  Hui Yang  2 ,  Yun Chen  1 ,  Yingrui Shi  4
Affiliations
  • 1. Department of Pharmacy, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013 Changsha, Hunan, China.
  • 2. The First Hospital of Hunan University of Chinese Medicine, 410007 Changsha, Hunan, China.
  • 3. The Second Department of Breast Surgery, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013 Changsha, Hunan, China.
  • 4. Department of Radiation Oncology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410013 Changsha, Hunan, China.
PMID: 38062826 DOI: 10.31083/j.fbl2811311
Abstract

Background: Breast cancer-related depression (BCRD) is strongly associated with BC and increases recurrence and mortality. This study investigated the role of kaempferol in the pathogenesis of BCRD and its underlying mechanism.

Methods: 4T1 mouse BC cells were treated with corticosterone (Cort) in vitro to develop a neuronal injury model, and a BCRD mouse model was established by injecting 4T1 cells and Cort. The effects of kaempferol on 4T1 cells and BCRD models were measured by behavioral tests, Cell Counting Kit-8 assay, wound healing assay, colony formation assay, Western blot analysis, quantitative Real-Time PCR, hematoxylin and eosin staining, enzyme-linked immunosorbent assay, and immunofluorescence. BCRD cells were transfected with the cyclo-oxygenase-2 (COX-2) overexpression plasmid to study the role of the COX-2/prostaglandin E2 (PGE2) axis in the anti-BCRD activity of kaempferol. The connection between kaempferol and COX-2 was analyzed by molecular docking.

Results: Kaempferol reduced the viability, migration, and clones of 4T1 cells and inhibited BC growth and depression-like behavior in mice. Kaempferol alleviated inflammation in BCRD, decreased interleukin 1 beta (IL-1β) and IL-6 levels, and increased transforming growth factor beta 1 (TGF-β1) and IL-10 levels. In addition, kaempferol elevated the levels of serotonin, dopamine, and norepinephrine and the amount of 5-Bromo-2'-deoxyuridine/neuronal nuclei-positive cells. Kaempferol downregulated COX-2 and PGE2, and kaempferol could DOCK with the protein structure of COX-2. Overexpression of COX-2 reduced BCRD viability, upregulated IL-1β and IL-6 levels, and downregulated TGF-β1 and IL-10 expression. Overexpression of COX-2 reversed the protective effects of kaempferol.

Conclusion: Kaempferol exerted anti-BCRD effects, at least in part by inhibiting the COX-2/PGE2 pathway, which regulates neuroinflammation, neurotransmitter imbalance, and defective neurogenesis. Therefore, kaempferol may be a promising candidate active ingredient for treating BCRD.

Keywords
COX-2; PGE2; breast cancer; depression; kaempferol.
Products