Dual targeting of mTORC1 and mTORC2 by INK-128 potently inhibits human prostate cancer cell growth in vitro and in vivo
Dual targeting of mTORC1 and mTORC2 by INK-128 potently inhibits human prostate cancer cell growth in vitro and in vivo
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DOI：
10.1007/s13277-015-3536-6
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发表时间：
2015-09-01
期刊：
影响因子：
--
通讯作者：
Wang, Shuo
中科院分区：
文献类型：
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作者：
Jiang, Shang-jun;Wang, Shuo
哺乳动物雷帕霉素靶蛋白（mTOR）复合物1和2（mTORC 1/2）在前列腺癌细胞中经常被过度激活，并与癌症进展相关。在目前的研究中，我们评估了潜在的抗前列腺癌活性的INK-128，ATP竞争性mTORC 1/2双重抑制剂，在体外和体内。我们的结果显示，INK-128通过诱导细胞凋亡在建立的（PC-3和LNCaP系）和原代（患者来源的）人前列腺癌细胞中发挥有效的抗增殖活性。后者通过膜联蛋白V百分比的增加、细胞质组蛋白相关DNA片段的形成和半胱天冬酶-3的裂解来证明。用泛半胱天冬酶抑制剂z-VAD-FMK或特异性半胱天冬酶-3抑制剂z-DVED-FMK预处理细胞后，INK-128诱导的前列腺癌细胞凋亡和细胞毒性减轻。在分子水平上，INK-18阻断了PC-3细胞和LNCaP细胞中的mTORC 1/2激活，并下调了mTOR调节的基因，包括细胞周期蛋白D1、缺氧诱导因子1 α（HIF-1 α）和HIF-2 α。然而，ERK-MAPK活化和雄激素受体表达不受INK-128处理的影响。在体内，口服INK-128可显着抑制裸小鼠PC-3异种移植物的生长。这项研究的临床前结果表明，INK-128可以作为一种有前途的抗前列腺癌药物进行进一步研究。
Both mammalian target of rapamycin (mTOR) complexes 1 and 2 (mTORC1/2) are often over-activated in prostate cancer cells and are associated with cancer progression. In the current study, we evaluated the potential anti-prostate cancer activity of INK-128, an ATP-competitive mTORC1/2 dual inhibitor, both in vitro and in vivo. Our results showed that INK-128 exerted potent anti-proliferative activity in established (PC-3 and LNCaP lines) and primary (patient-derived) human prostate cancer cells by inducing cell apoptosis. The latter was evidenced by increase of annexin V percentage, formation of cytoplasmic histone-associated DNA fragments, and cleavage of caspase-3. INK-128-induced prostate cancer cell apoptosis and cytotoxicity were alleviated upon pretreatment of cells with the pan-caspase inhibitor z-VAD-FMK or the specific caspase-3 inhibitor z-DVED-FMK. At the molecular level, INK-18 blocked mTORC1/2 activation in PC-3 cells and LNCaP cells and downregulated mTOR-regulated genes including cyclin D1, hypoxia-inducible factor 1 alpha (HIF-1 alpha), and HIF-2 alpha. ERK-MAPK activation and androgen receptor expression were, however, not affected by INK-128 treatment. In vivo, oral administration of INK-128 significantly inhibited growth of PC-3 xenografts in nude mice. The preclinical results of this study suggest that INK-128 could be further investigated as a promising anti-prostate cancer agent.