Berberine and Emodin abrogates breast cancer growth and facilitates apoptosis through inactivation of SIK3-induced mTOR and Akt signaling pathway
Berberine and Emodin abrogates breast cancer growth and facilitates apoptosis through inactivation of SIK3-induced mTOR and Akt signaling pathway
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DOI：
10.1016/j.bbadis.2020.165897
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发表时间：
2020-11-01
影响因子：
6.2
通讯作者：
Manoharan, Ravi
中科院分区：
文献类型：
--
作者：
Ponnusamy, Lavanya;Kothandan, Gugan;Manoharan, Ravi
盐诱导激酶3（SIK3）属于AMPK相关激酶家族，其参与细胞代谢、细胞极性重塑和上皮-间充质转化的调节。乳腺癌细胞中SIK3表达升高有助于肿瘤发生;然而，其潜在机制仍有待阐明。在这项研究中，我们证明了SIK3表达上调，同时SIK3的高表达与乳腺癌的生存率低有关。具体而言，SIK3敲低揭示了SIK3是mTOR/Akt信号通路和乳腺癌细胞增殖所必需的。此外，我们的研究结果表明，大黄素（EMO）联合小檗碱（BBR）显着抑制SIK3活性，导致乳腺癌细胞生长减少，细胞周期阻滞和凋亡增加，但在非恶性乳腺上皮细胞系。机制研究进一步揭示，EMO和BBR联合治疗抑制乳腺癌细胞中SIK3增强的mTOR介导的有氧糖酵解和细胞生长。此外，联合治疗减弱Akt信号传导，从而以SIK3依赖性方式诱导乳腺癌细胞的G0/G1期细胞周期停滞和凋亡。CRISPR/Cas9或siRNA介导的SIK3敲除/敲低在管腔和基底样乳腺癌中均显示出相反的趋势。总的来说，我们的研究结果表明，EMO和BBR的组合减弱了乳腺癌中SIK3驱动的肿瘤生长，因此，EMO和BBR可能是一种新的SIK3抑制剂，可用于预防乳腺癌。
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.