Harmine Hydrochloride Mediates the Induction of G2/M Cell Cycle Arrest in Breast Cancer Cells by Regulating the MAPKs and AKT/FOXO3a Signaling Pathways

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-11, Vol.26 (21), p.6714
• Main Authors: Ock, Chae Won, Kim, Gi Dae
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; AKT/FOXO3a; Apoptosis; Biological activity; Breast cancer; Breast Neoplasms; c-Jun protein; Cancer therapies; Cdc2 protein; Cell cycle; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cyclin B1; Cyclin-dependent kinases; Drug dosages; Female; Forkhead Box Protein O3 - metabolism; FOXO3 protein; G2 Phase Cell Cycle Checkpoints - drug effects; G2/M cell cycle arrest; Gastric cancer; Harmine - chemistry; Harmine - pharmacology; harmine hydrochloride; Humans; JNK protein; Kinases; Medical prognosis; Mitogen-Activated Protein Kinases - metabolism; Molecular Structure; Natural products; p53 Protein; Phosphorylation; Protein kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Regulation; Side effects; Signal transduction; Signal Transduction - drug effects; TOR protein; Transcription factors; Wound healing
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26216714

Breast cancer (BC) is one of the most common causes of death among women worldwide. Recently, interest in novel approaches for BC has increased by developing new drugs derived from natural products with reduced side effects. This study aimed to treat BC cells with harmine hydrochloride (HMH) to identify its anticancer effects and mechanisms. HMH treatment suppressed cell growth, migration, invasion, and colony formation in MCF-7 and MDA-MB-231 cells, regardless of the hormone signaling. It also reduced the phosphorylation of PI3K, AKT, and mTOR and increased FOXO3a expression. Additionally, HMH treatment increased p38 phosphorylation in MCF-7 cells and activated c-Jun N-terminal kinase (JNK) phosphorylation in MDA-MB-231 cells in a dose-dependent manner, where activated p38 and JNK increased FOXO3a expression. Activated FOXO3a increased the expression of p53, p21, and their downstream proteins, including p-cdc25, p-cdc2, and cyclin B1, to induce G2/M cell cycle arrest. Furthermore, HMH inhibited the PI3K/AKT/mTOR pathway by significantly reducing p-AKT expression in combination with LY294002, an AKT inhibitor. These results indicate that mitogen-activated protein kinases (MAPKs) and AKT/FOXO3a signaling pathways mediate the induction of cell cycle arrest following HMH treatment. Therefore, HMH could be a potential active compound for anticancer bioactivity in BC cells.