ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo.
ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo.
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DOI：
10.18632/oncotarget.18303
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发表时间：
2017-10-10
期刊：
影响因子：
--
通讯作者：
Yin G
中科院分区：
文献类型：
--
作者：
Yin G;Fan J;Zhou W;Ding Q;Zhang J;Wu X;Tang P;Zhou H;Wan B;Yin G
mTOR是骨肉瘤的一个有价值的癌靶点。评价了新型mTOR激酶抑制剂CZ 415的抗骨肉瘤活性。我们证明了CZ 415有效地抑制已知的骨肉瘤细胞系（U2 OS、MG-63和SaOs 2）和原代人骨肉瘤细胞的存活和增殖。此外，CZ 415引起骨肉瘤细胞凋亡并破坏细胞周期进程。在骨肉瘤细胞中的CZ 415处理同时阻断mTORC 1和mTORC 2活化。有趣的是，ERK-MAPK活化可能是CZ 415的主要抗性因素。ERK抑制（通过MEK 162/U 0126）或敲低（通过靶向ERK 1/2 shRNA）显著敏化CZ 415诱导的骨肉瘤细胞凋亡。在体内，CZ 415口服给药有效地抑制小鼠中的U2 OS肿瘤生长。其活性随着MEK 162的共同施用而进一步增强。总的来说，我们证明了ERK抑制敏感CZ 415诱导的抗骨肉瘤活性在体外和体内。CZ 415可以作为一种有前途的抗骨肉瘤剂，单独或与ERK抑制剂组合进行进一步测试。
mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415. ERK inhibition (by MEK162/U0126) or knockdown (by targeted ERK1/2 shRNAs) dramatically sensitized CZ415-induced osteosarcoma cell apoptosis. In vivo, CZ415 oral administration efficiently inhibited U2OS tumor growth in mice. Its activity was further potentiated with co-administration of MEK162. Collectively, we demonstrate that ERK inhibition sensitizes CZ415-induced anti-osteosarcoma activity in vitro and in vivo. CZ415 could be further tested as a promising anti-osteosarcoma agent, alone or in combination of ERK inhibition.
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