Asperolide A prevents bone metastatic breast cancer via the PI3K/AKT/mTOR/c-Fos/NFATc1 signaling pathway.
Asperolide A prevents bone metastatic breast cancer via the PI3K/AKT/mTOR/c-Fos/NFATc1 signaling pathway.
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Asperolide A 通过 PI3K/AKT/mTOR/c-Fos/NFATc1 信号通路预防骨转移性乳腺癌
DOI：
10.1002/cam4.3432
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发表时间：
2020-11
期刊：
影响因子：
4
通讯作者：
Jiao B
中科院分区：
文献类型：
--
作者：
Jiang W;Rixiati Y;Huang H;Shi Y;Huang C;Jiao B
乳腺癌是全世界恶性肿瘤妇女死亡的主要原因。骨转移是影响乳腺癌预后的主要因素。因此，迫切需要抗肿瘤和抗乳腺癌诱导的溶骨剂。我们在体外研究了海洋来源的药物Asperolide A （AA）对骨溶解和RANKL诱导的磷酸肌苷3激酶(PI3K)/AKT/mTOR/c - FOS/核因子活化T细胞1 （NFATc1）途径激活、F - actin环形成和活性氧（ROS）生成的影响。我们通过CCK8实验、伤口愈合实验、transwell实验、细胞凋亡Annexin V‐FITC/PI染色和细胞周期实验来评估AA对乳腺癌MDA‐MB‐231和MDA‐MB‐436细胞的体外作用。此外，我们使用乳腺癌诱导的骨溶解裸鼠模型评估了AA在体内的作用，随后进行了微计算机断层扫描，酒石酸盐抗性酸性磷酸酶染色，苏木精和伊红染色。Asperolide A在体外以剂量依赖的方式抑制破骨细胞的形成和分化、骨吸收、F - actin带的形成、ROS活性和破骨细胞特异性基因和蛋白的表达，并阻止PI3K/AKT/mTOR/c - FOS/NFATc1信号的激活。AA还通过减少破骨细胞的形成和功能以及灭活PI3K/AKT/mTOR信号来抑制乳腺癌的生长和乳腺癌诱导的骨溶解。我们的研究表明，AA抑制骨转移性乳腺癌。这些发现表明AA是治疗骨转移性乳腺癌的一种潜在的新型治疗药物。我们的研究表明，曲霉内酯A （AA）抑制乳腺癌诱导的骨质疏松症。这些发现表明，AA是一种潜在的新型治疗乳腺癌骨转移的候选药物。
Breast cancer is the leading cause of death among women with malignant tumors worldwide. Bone metastasis is the main factor affecting the prognosis of breast cancer. Therefore, both antitumor and anti‐breast‐cancer‐induced osteolysis agents are urgently needed. We examined the effect of Asperolide A (AA), a marine‐derived agent, on osteolysis and RANKL‐induced phosphoinositide 3‐kinase (PI3K)/AKT/mTOR/c‐FOS/nuclear factor‐activated T cell 1 (NFATc1) pathway activation, F‐actin ring formation, and reactive oxygen species (ROS) generation in vitro. We evaluated AA effect on breast cancer MDA‐MB‐231 and MDA‐MB‐436 cells in vitro through CCK8 assay, wound healing assay, transwell assay, Annexin V‐FITC/PI staining for cell apoptosis, and cell cycle assay. Furthermore, we assessed the effect of AA in vivo using a breast cancer‐induced bone osteolysis nude mouse model, followed by micro‐computed tomography, tartrate‐resistant acid phosphatase staining, and hematoxylin and eosin staining. Asperolide A inhibited osteoclast formation and differentiation, bone resorption, F‐actin belt formation, ROS activity, and osteoclast‐specific gene and protein expressions and prevented PI3K/AKT/mTOR/c‐FOS/NFATc1 signaling activation in a dose‐dependent manner in vitro. AA also inhibited breast cancer growth and breast cancer‐induced bone osteolysis by reducing osteoclast formation and function and inactivated PI3K/AKT/mTOR signaling in vivo. Our study demonstrated that AA suppressed bone metastatic breast cancer. These findings indicate AA as a potential, novel curative drug candidate for patients with bone metastatic breast cancer. Our study showed that Asperolide A (AA) repressed breast cancer‐induced osteoporosis. These findings indicate AA as a potential, novel curative drug candidate for breast cancer patients with bone metastases.
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作者：
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