Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A
Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A
复制标题
STAT3 磷酸化减弱促进 Raddeanin A 诱导的人骨肉瘤细胞凋亡和化疗敏感性。
DOI：
10.7150/ijbs.30168
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Cai, Zhengdong
中科院分区：
文献类型：
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作者：
Wang, Zhuoying;Wang, Chongren;Cai, Zhengdong
骨肉瘤是青少年最常见的原发性骨恶性肿瘤。目前OS治疗的一个主要障碍是耐药性。Raddeanin A（RA）是一种齐墩果烷型三萜皂苷，在多种肿瘤模型中发挥抗肿瘤作用，但RA在人类耐药OS中的作用仍有待阐明。本研究旨在探讨RA对OS细胞的抗肿瘤作用及其机制。RA抑制细胞增殖和集落形成，并诱导细胞凋亡，在药物敏感和耐药细胞的剂量依赖性方式。此外，RA暴露导致抑制白细胞介素-6（IL-6）诱导的JAK 2/STAT 3信号通路激活和靶基因表达的药物敏感和耐药细胞。同时，我们观察到与亲代细胞相比，耐药OS细胞中MDR 1和STAT 3的表达显著增加。STAT 3过表达促进了药物敏感OS细胞和药物耐药OS细胞中的化疗耐药性和MDR 1蛋白表达，而用siRNA抑制STAT 3则使OS细胞对阿霉素处理敏感。此外，RA通过增加其细胞摄取、消融外排和下调耐药细胞中的MDR 1以及减弱STAT 3磷酸化而协同增加阿霉素毒性。最后，RA抑制体内肿瘤生长和诱导凋亡的裸鼠耐药OS胫骨原位模型。综上所述，RA是治疗OS中多柔比星耐药性的有希望的潜在治疗剂。
Osteosarcoma (OS) is the most common primary bone malignancy in adolescents. One major obstacle for current OS treatment is drug-resistance. Raddeanin A (RA), an oleanane-type triterpenoid saponin, exerts anti-tumor effects in several tumor models, but the effect of RA in human drug-resistant OS remained to be elucidated. In the present study, we investigated the anti-tumor effects of RA in both drug-sensitive and drug-resistant OS cells and its underlying mechanism. RA inhibited cell proliferation and colony formation and induced apoptotic cell death in a dose-dependent manner in both drug-sensitive and drug-resistant cells. Moreover, RA exposure resulted in the inhibition of interleukin-6 (IL-6)-induced JAK2/STAT3 signaling pathway activation and target gene expression in both drug-sensitive and drug-resistant cells. Meanwhile, we observed significantly increased MDR1 and STAT3 expression in drug-resistant OS cells compared with parental cells. STAT3 overexpression promoted chemo-resistance and MDR1 protein expression in both drug-sensitive OS cells and drug-resistant OS cells, while inhibiting STAT3 with siRNA sensitized OS cells to doxorubicin treatment. In addition, RA synergistically increased doxorubicin toxicity by increasing its cellular uptake, ablating efflux and downregulating MDR1 in drug-resistant cells with attenuation of STAT3 Phosphorylation. Finally, RA suppressed in vivo tumor growth and induced apoptosis in nude mouse using drug-resistant OS tibia orthotopic model. Taken together, RA is a promising potential therapeutic for the treatment of doxorubicin resistance in OS.