Phosphatidylinositol 3-kinase beta and delta isoforms play key roles in metastasis of prostate cancer DU145 cells.
Phosphatidylinositol 3-kinase beta and delta isoforms play key roles in metastasis of prostate cancer DU145 cells.
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磷脂酰肌醇 3-激酶 β 和 δ 亚型在前列腺癌 DU145 细胞的转移中发挥关键作用。
DOI：
10.1096/fj.201800183r
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Kong Dexin
中科院分区：
文献类型：
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作者：
Zhang Zhe;Liu Jie;Wang Yingying;Tan Xiao;Zhao Wennan;Xing Xiaoxue;Qiu Yuling;Wang Ran;Jin Meihua;Fan Guanwei;Zhang Ping;Zhong Yuxu;Kong Dexin
转移是前列腺癌致死的主要原因。I类磷脂酰肌醇3-激酶(PI3K)包括α，β，δ和γ四种亚型，在细胞的生长、迁移、侵袭等过程中发挥重要作用。然而，每种PI3K亚型在癌细胞迁移和侵袭中各自的作用尚不清楚。在一项旨在阐明4种PI3K亚型各自作用的研究中，我们研究了每种PI3K亚型特异性抑制剂处理DU145细胞后迁移和侵袭能力的变化。PI3Kβ抑制剂(GSK2636771和TGX221)和PI3Kδ抑制剂(CAL101和IC87114)均能有效地阻断DU145细胞的迁移和侵袭，而PI3Kα抑制剂BYL719和PI3Kγ抑制剂AS252424对DU145细胞的迁移和侵袭无明显影响。此外，敲除PI3Kβ或PI3Kδ亚型可显著减少DU145的迁移量。结果提示，PI3Kβ和PI3Kδ在前列腺癌细胞迁移中起关键作用，而PI3Kα和PI3Kγ可能是多余的。口服GSK2636771(100 mg/kg)和CAL101(30 mg/kg)可抑制DU145细胞骨内注射的骨肿瘤生长，并能改善骨结构和骨密度。组织染色显示，与未治疗组相比，GSK2636771和CAL101治疗组小鼠骨骼中转移的DU145细胞和破骨细胞减少。综上所述，我们的结果表明了4种PI3K亚型在前列腺癌DU145细胞迁移中的不同作用，并证明了PI3K-亚型特异性抑制剂在体外和体内的抗转移作用，其中大多数正在进行临床试验。D.磷脂酰肌醇3-激酶β和δ亚型在前列腺癌DU145细胞转移中起关键作用.Www.fasebj.org
Metastasis is the main cause of the lethality of prostate cancer. Class I phosphatidylinositol 3‐kinases (PI3Ks), which contain 4 isoforms, α, β, δ, and γ, are known to play important roles in cell growth, migration, invasion, and so on. However, the respective role of each PI3K isoform in cancer cell migration and invasion remains unknown. In a study that aimed to elucidate the respective role of the 4 PI3K isoforms, we investigated the change in migratory and invasive ability of DU145 cells after treatment with each PI3K isoform‐specific inhibitor. Both migration and invasion of DU145 cells were potently blocked by each of the PI3Kβ inhibitors (GSK2636771 and TGX221) and PI3Kδ inhibitors (CAL101 and IC87114) while not obviously affected by PI3Kα inhibitor BYL719 or PI3Kγ inhibitor AS252424. Furthermore, knocking down PI3Kβ or PI3Kδ isoform led to a significant decrease in migration of DU145. The results suggest that PI3Kβ and PI3Kδ play key roles in prostate cancer cell migration, while PI3Kα and PI3Kγ might be redundant. Oral administration of GSK2636771 (100 mg/kg) and CAL101 (30 mg/kg) inhibited tumor growth in bone, an experimental model by intratibia injection of DU145 cells, with improved bone structure and bone mineral density analyzed by micro‐computed tomography. Tissue staining indicated reduction of metastatic DU145 cells and osteoclasts in the bones of GSK2636771‐ and CAL101‐treated mice compared to the untreated group. In summary, our results indicated the distinct roles of 4 PI3K isoforms in the migration of prostate cancer DU145 cells, and they demonstrated thein vitroandin vivoantimetastatic effect of PI3K‐isoform specific inhibitors, most of which are in clinical trials.—Zhang, Z., Liu, J., Wang, Y., Tan, X., Zhao, W., Xing, X., Qiu, Y., Wang, R., Jin, M., Fan, G., Zhang, P., Zhong, Y., Kong, D. Phosphatidylinositol 3‐kinase β and δ isoforms play key roles in metastasis of prostate cancer DU145 cells.FASEB J. 32, 5967–5975 (2018). www.fasebj.org