Berberine and Emodin abrogates breast cancer growth and facilitates apoptosis through inactivation of SIK3-induced mTOR and Akt signaling pathway
| Autor: | Lavanya Ponnusamy, Gugan Kothandan, Ravi Manoharan |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Emodin Cell cycle checkpoint Berberine Cell Survival Blotting Western Apoptosis Breast Neoplasms medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Breast cancer Cell Line Tumor medicine Humans Clustered Regularly Interspaced Short Palindromic Repeats RNA Small Interfering Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Kinase Akt/PKB signaling pathway Cell growth Chemistry Cell Cycle medicine.disease Gene Expression Regulation Neoplastic 030104 developmental biology 030220 oncology & carcinogenesis MCF-7 Cells Cancer research Molecular Medicine Female Carcinogenesis Protein Kinases Signal Transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1866:165897 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2020.165897 |
| Popis: | Salt-inducible kinases 3 (SIK3) belong to the AMPK-related family of kinases, which have been implicated in the regulation of cell metabolism, cell polarity remodelling, and epithelial-mesenchymal transition. Elevated SIK3 expressions in breast cancer cells are shown to contribute to tumorigenesis; however, the underlying mechanism remains to be elucidated. In this study, we demonstrate that SIK3 expression is upregulated and concurrently high expression of SIK3 is associated with poor survival in breast cancer. Specifically, SIK3 knockdown revealed that SIK3 is required for the mTOR/Akt signaling pathway and proliferation of breast cancer cells. Furthermore, our findings showed that Emodin (EMO) combined with Berberine (BBR) significantly inhibited SIK3 activity, leading to reduced cell growth, increased cell cycle arrest and apoptosis in breast cancer cells, but not in non-malignant breast epithelial cell line. Mechanistic studies further reveal that EMO and BBR in combined treatment inhibited SIK3-potentiated mTOR-mediated aerobic glycolysis and cell growth in breast cancer cells. Moreover, combination treatments attenuate Akt signaling, thereby inducing G0/G1 phase cell cycle arrest and apoptosis of breast cancer cells in a SIK3-dependent manner. CRISPR/Cas9 or siRNA-mediated SIK3 knockout/knockdown showed an opposite trend in both the luminal and basal-like breast cancer. Collectively, our findings reveal that combination of EMO and BBR attenuates SIK3-driven tumor growth in breast cancer, and thus, EMO and BBR might be a novel SIK3 inhibitor explored into the prevention of breast cancer. |
| Databáze: | OpenAIRE |
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