YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells.
YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells.
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DOI：
10.1371/journal.pone.0182149
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wu CW
中科院分区：
文献类型：
--
作者：
Cheng CC;Chang J;Huang SC;Lin HC;Ho AS;Lim KH;Chang CC;Huang L;Chang YC;Chang YF;Wu CW
肿瘤干细胞存活是肿瘤抑制治疗后肿瘤复发的主要因素。因此，必须发现特异性和有效的癌症干性抑制剂以减少肿瘤复发。YM 155已被指示显著减少干细胞来源的肿瘤球形成。然而，YM 155对抗癌症干性的药物机制尚不清楚。本研究探讨YM 155抗肺癌癌干化的可能机制。将来源于表皮生长因子受体（EGFR）突变型HCC 827和EGFR野生型A549细胞的肿瘤球用作癌症干性模型，这些细胞表达较高的癌症干性标志物（CD 133、Oct 4和Nanog）。我们观察到EGFR自磷酸化（Y1068）在HCC 827和A549衍生的肿瘤球中比在亲本细胞中更高;这种自磷酸化通过激活G9 a介导的干性诱导肿瘤球形成。值得注意的是，YM 155通过阻断EGFR的自磷酸化和EGFR-G9 a介导的干性途径来抑制肿瘤球形成。EGFR和G9 a的化学和遗传抑制揭示了EGFR-G9 a途径在维持癌症干性性质中的重要作用。总之，这项研究不仅揭示了EGFR可以通过提高G9 a介导的干细胞性来触发肿瘤球形成，而且还证明了YM 155可以通过同时阻断EGFR自磷酸化和G9 a活性来抑制这种形成，从而作为一种有效的抗肺癌干细胞性的药物。
Cancer stem cell survival is the leading factor for tumor recurrence after tumor-suppressive treatments. Therefore, specific and efficient inhibitors of cancer stemness must be discovered for reducing tumor recurrence. YM155 has been indicated to significantly reduce stemness-derived tumorsphere formation. However, the pharmaceutical mechanism of YM155 against cancer stemness is unclear. This study investigated the potential mechanism of YM155 against cancer stemness in lung cancer. Tumorspheres derived from epidermal growth factor receptor (EGFR)-mutant HCC827 and EGFR wild-type A549 cells expressing higher cancer stemness markers (CD133, Oct4, and Nanog) were used as cancer stemness models. We observed that EGFR autophosphorylation (Y1068) was higher in HCC827- and A549-derived tumorspheres than in parental cells; this autophosphorylation induced tumorsphere formation by activating G9a-mediated stemness. Notably, YM155 inhibited tumorsphere formation by blocking the autophosphorylation of EGFR and the EGFR-G9a-mediated stemness pathway. The chemical and genetic inhibition of EGFR and G9a revealed the significant role of the EGFR-G9a pathway in maintaining the cancer stemness property. In conclusion, this study not only revealed that EGFR could trigger tumorsphere formation by elevating G9a-mediated stemness but also demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B
影响因子：
2
作者：
Kellner S;Kikyo N
通讯作者：
Kikyo N
影响因子：
29.4
作者：
Li L;Hao X;Qin J;Tang W;He F;Smith A;Zhang M;Simeone DM;Qiao XT;Chen ZN;Lawrence TS;Xu L
通讯作者：
Xu L
生存素抑制剂 YM155 可抑制小鼠胃癌异种移植物的生长，而不影响正常组织。
影响因子：
--
作者：
Cheng XJ;Lin JC;Ding YF;Zhu L;Ye J;Tu SP
通讯作者：
Tu SP