The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation
The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation
复制标题
PI3Kα 抑制剂 DFX24 通过 ERK 抑制和 EPHB6 重新激活抑制非小细胞肺癌的肿瘤生长和转移
DOI：
10.1016/j.phrs.2020.105147
复制
发表时间：
2020-10-01
影响因子：
9.3
通讯作者：
Lee, Sang Kook
中科院分区：
文献类型：
--
作者：
Fan, Yan-Hua;Ding, Huai-Wei;Lee, Sang Kook
EPHB6是一种转移抑制基因，在非小细胞肺癌（NSCLC）中经常减少或缺乏，从而导致远处转移的发生。这表明EPHB6的再激活可能会阻止NSCLC的转移。然而，EPHB6的表达除了抑制癌细胞的迁移和侵袭外，还可能通过激活Akt和ERK通路来促进癌细胞的生长和抑制细胞凋亡。在本研究中，我们开发了一种新的喹唑啉-4(3H)- 1类似物（DFX24）作为潜在的PI3K α抑制剂，可以抑制非小细胞肺癌细胞系的细胞增殖和转移。分子机制研究发现，DFX24通过抑制PI3K α和ERK活性，以及增加EPHB6的表达来抑制细胞生长和转移。此外，DFX24还分别通过抑制PI3K/Akt通路和激活线粒体依赖通路诱导细胞周期阻滞和肿瘤细胞凋亡。这些发现表明，DFX24可能被认为是一种新的候选药物，并可能为非小细胞肺癌提供潜在的治疗方法。
EPHB6 is a metastasis inhibitory gene that is frequently decreased or deficiency in non-small cell lung cancer (NSCLC), which contributed to the subsequent development of distant metastasis. These suggested the possibility that reactivation of EPHB6 might prevent the metastasis of NSCLC. Nevertheless, EPHB6 expression might also promote cancer cell growth and inhibit cell apoptosis by activating Akt and ERK pathway, apart from inhibition of migration and invasion. In the present study, we developed a novel quinazolin-4(3H)-one analog (DFX24) as a potential PI3K alpha inhibitor, which inhibited both cell proliferation and metastasis of NSCLC cell lines. Investigation to the molecular mechanisms revealed DFX24 inhibited the cell growth and metastasis via inhibition of PI3K alpha and ERK activity, as well as the increase in EPHB6 expression. In addition, DFX24 also induced cell cycle arrest and tumor cell apoptosis by inhibiting PI3K/Akt pathway and activating mitochondria-dependent pathway, respectively. These findings suggested that DFX24 might be considered as a novel drug candidate and may provide a potential therapy for NSCLC.