Paeoniflorin Sensitizes Breast Cancer Cells to Tamoxifen by Downregulating microRNA-15b via the FOXO1/CCND1/β-Catenin Axis.

Abstract

BACKGROUND:

Paeoniflorin (Pae) possesses anti-tumor activity in various malignancies. However, it is unclear whether Pae plays a sensitizer role in breast cancer (BC) and the molecular mechanisms involved in this process. Our oligonucleotide microarray revealed that microRNA (miR)-15b is the most significantly downregulated miRNA in MCF-7/4-hydroxytamoxifen (4-OHT) cells treated with Pae. This paper summarized the relevance of Pae in BC cell endocrine resistance to tamoxifen (Tam) and the molecular mechanisms involved miR-15b expression.

MATERIALS AND METHODS:

4-OHT-resistant BC cell lines were developed and treated with different concentrations of Pae. Flow cytometry, lactose dehydrogenase activity, caspase-3 activity, colony formation, and EdU assays were carried out to assess the impact of Pae on BC cells. Differentially expressed miRNAs in BC cells treated with Pae were analyzed by microarray. Targeting mRNAs of screened miR-15b as well as the binding of forkhead box O1 (FOXO1) to the cyclin D1 (CCND1) promoter sequence were predicted through bioinformatics analysis. Finally, the expression of β-catenin signaling-related genes in cells was detected by Western blotting.

RESULTS:

Pae (100 μg/mL) inhibited the clonality and viability of BC cells, while enhancing apoptosis in vitro. Pae also repressed miR-15b expression. Overexpression of miR-15b restored the growth and resistance of BC cells to 4-OHT. Moreover, Pae promoted FOXO1 expression by downregulating miR-15b, thereby transcriptionally inhibiting CCND1 and subsequently blocking β-catenin signaling.

CONCLUSION:

Pae inhibits 4-OHT resistance in BC cells by regulating the miR-15b/FOXO1/CCND1/β-catenin pathway.

• Authors: Yanhong Wang, Qian Wang, Xibei Li, Gongwen Luo, Mou Shen, Jia Shi, Xueliang Wang, Lu Tang
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 15 Pg. 245-257 ( 2021) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 33519190 (Publication Type: Journal Article)
• Copyright: © 2021 Wang et al.

Chemical References

• Antineoplastic Agents
• CCND1 protein, human
• CTNNB1 protein, human
• FOXO1 protein, human
• Forkhead Box Protein O1
• Glucosides
• MIRN15 microRNA, human
• MicroRNAs
• Monoterpenes
• beta Catenin
• Tamoxifen
• Cyclin D1
• peoniflorin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclin D1 (antagonists & inhibitors, genetics, metabolism)
• Down-Regulation (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Forkhead Box Protein O1 (antagonists & inhibitors, genetics, metabolism)
• Glucosides (pharmacology)
• Humans
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• Monoterpenes (pharmacology)
• Tamoxifen (pharmacology)
• Tumor Cells, Cultured
• beta Catenin (antagonists & inhibitors, genetics, metabolism)