Natural product pectolinarigenin inhibits osteosarcoma growth and metastasis via SHP-1-mediated STAT3 signaling inhibition.
Natural product pectolinarigenin inhibits osteosarcoma growth and metastasis via SHP-1-mediated STAT3 signaling inhibition.
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天然产物果胶苷元通过 SHP-1 介导的 STAT3 信号抑制抑制骨肉瘤生长和转移
DOI：
10.1038/cddis.2016.305
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发表时间：
2016-10-13
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
信号转导子和转录激活子 3 (STAT3) 在癌症侵袭性中发挥重要作用，并已被证实是癌症治疗的一个有吸引力的靶点。在这项研究中，我们使用双荧光素酶测定来鉴定果胶苷元抑制 STAT3 活性。进一步的研究表明，果胶苷元可抑制骨肉瘤细胞中组成型和白细胞介素 6 诱导的 STAT3 信号传导，减少 STAT3 在细胞核中的积累，并阻断 STAT3 DNA 结合活性。机制研究表明，果胶苷元干扰了SHP-1启动子区STAT3/DNA甲基转移酶1/HDAC1组蛋白脱乙酰酶1复合物的形成，从而反向介导STAT3信号传导，导致骨肉瘤中SHP-1表达上调。我们还发现果胶苷元显着抑制骨肉瘤细胞增殖，诱导细胞凋亡并降低 STAT3 下游蛋白细胞周期蛋白 D1、生存素、B 细胞淋巴瘤 2 (Bcl-2)、B 细胞淋巴瘤特大 (Bcl-xl) 和骨髓细胞白血病 1 (Mcl-1) 的水平。此外，果胶苷元还能抑制骨肉瘤细胞的迁移、侵袭和保留上皮间质转化（EMT）表型。在骨肉瘤的自发和患者来源的异种移植模型中，我们发现（腹膜内）给予果胶苷元（20 mg/kg/2 天和 50 mg/kg/2 天）可阻断 STAT3 激活并损害肿瘤生长和转移，并具有优异的药效学特性。综上所述，我们的研究结果表明，果胶苷元可能是骨肉瘤干预的候选者，与其 STAT3 信号传导抑制活性有关。
Signal transducer and activator of transcription 3 (STAT3) has important roles in cancer aggressiveness and has been confirmed as an attractive target for cancer therapy. In this study, we used a dual-luciferase assay to identify that pectolinarigenin inhibited STAT3 activity. Further studies showed pectolinarigenin inhibited constitutive and interleukin-6-induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus and blocked STAT3 DNA-binding activity in osteosarcoma cells. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNA methyltransferase 1/HDAC1 histone deacetylase 1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma cell proliferation, induced apoptosis and reduced the level of STAT3 downstream proteins cyclin D1, Survivin, B-cell lymphoma 2 (Bcl-2), B-cell lymphoma extra-large (Bcl-xl) and myeloid cell leukemia 1 (Mcl-1). In addition, pectolinarigenin inhibited migration, invasion and reserved epithelial–mesenchymal transition (EMT) phenotype in osteosarcoma cells. In spontaneous and patient-derived xenograft models of osteosarcoma, we identified administration (intraperitoneal) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and impaired tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity.
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影响因子：
11.2
作者：
Niinaka Y;Harada K;Fujimuro M;Oda M;Haga A;Hosoki M;Uzawa N;Arai N;Yamaguchi S;Yamashiro M;Raz A
通讯作者：
Raz A
APO2L/TRAIL对SCID小鼠中异种移植物的胰腺腺癌患者胰腺腺癌的抗肿瘤作用。
影响因子：
7.4
作者：
Hylander, BL;Pitoniak, R;Penetrante, RB;Gibbs, JF;Oktay, D;Cheng, JR;Repasky, EA
通讯作者：
Repasky, EA
影响因子：
20.3
作者：
Chim, CS;Fung, TK;Kwong, YL
通讯作者：
Kwong, YL
影响因子：
2
作者：
Lim, Hyun;Son, Kun Ho;Kim, Hyun Pyo
通讯作者：
Kim, Hyun Pyo
影响因子：
2.8
作者：
Hellsten, Rebecka;Johansson, Martin;Bjartell, Anders
通讯作者：
Bjartell, Anders