Targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin squamous cell carcinoma cell growth in vitro and in vivo
Targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin squamous cell carcinoma cell growth in vitro and in vivo
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LY3023414靶向PI3K-AKT-mTOR抑制人皮肤鳞状细胞癌细胞的体外和体内生长
DOI：
10.1016/j.bbrc.2017.06.052
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发表时间：
2017-08-19
影响因子：
3.1
通讯作者：
Wang, Xuemin
中科院分区：
文献类型：
--
作者：
Zou, Ying;Ge, Minggai;Wang, Xuemin
在人皮肤鳞状细胞癌中发现PI3K-AKT-mTOR信号异常激活。LY3023414是一种新型、高效、口服生物利用的PI3K-AKT-mTOR抑制剂。测定了其对人皮肤SCC细胞的杀伤活性。我们证明，当LY3023414加入已建立的(A431株)和原代(患者来源的)人皮肤SCC细胞时，具有细胞毒性。LY3023414诱导皮肤SCC细胞G0/1-S停滞，抑制细胞增殖。此外，LY3023414还可诱导皮肤SCC细胞中caspase-3/-9的激活和细胞凋亡。耐人寻味的是，LY3023414对正常人皮肤细胞(黑素细胞、角质形成细胞和成纤维细胞)既没有细胞毒性，也没有促凋亡作用。在分子水平上，LY3023414可使PI3K-AKT-mTOR底物P85、AKT和S6K1去磷酸化，从而阻断皮肤SCC细胞中PI3K-AKT-mTOR的激活。体内研究表明，口服耐受性良好的LY3023414可抑制严重联合免疫缺陷(SCID)小鼠的A431移植瘤生长。LY3023414处理的肿瘤中AKT-mTOR的激活也在很大程度上受到抑制。综上所述，这些结果表明，LY3023414靶向PI3K-AKT-mTOR在体内外抑制人皮肤SCC细胞的生长，为进一步的临床试验奠定了基础。(C)2017 Elsevier Inc.保留所有权利。
Abnormal activation of PI3K-AKT-mTOR signaling is detected in human skin squamous cell carcinoma (SCC). LY3023414 is a novel, potent, and orally bio-available PI3K-AKT-mTOR inhibitor. Its activity against human skin SCC cells was tested. We demonstrated that LY3023414 was cytotoxic when added to established (A431 line) and primary (patient-derived) human skin SCC cells. LY3023414 induced G0/1-S arrest and inhibited proliferation of skin SCC cells. Moreover, LY3023414 induced activation of caspase-3/-9 and apoptosis in skin SCC cells. Intriguingly, LY3023414 was yet non-cytotoxic nor pro-apoptotic to normal human skin cells (melanocytes, keratinocytes and fibroblasts). At the molecular level, LY3023414 blocked PI3K-AKT-mTOR activation in skin SCC cells, as it dephosphorylated PI3K-AKT-mTOR substrates: P85, AKT and S6K1. In vivo studies showed that oral administration of LY3023414 at well-tolerated doses inhibited A431 xenograft tumor growth in severe combined immunodeficiency (SCID) mice. AKT-mTOR activation in LY3023414-treated tumors was also largely inhibited. Together, these results suggest that targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin SCC cell growth in vitro and in vivo, establishing the rationale for further clinical testing. (C) 2017 Elsevier Inc. All rights reserved.