Synergistic Antitumor Effect of BKM120 with Prima-1Met Via Inhibiting PI3K/AKT/mTOR and CPSF4/hTERT Signaling and Reactivating Mutant P53.
Synergistic Antitumor Effect of BKM120 with Prima-1Met Via Inhibiting PI3K/AKT/mTOR and CPSF4/hTERT Signaling and Reactivating Mutant P53.
复制标题
BKM120 与 Prima-1Met 通过抑制 PI3K/AKT/mTOR 和 CPSF4/hTERT 信号传导和重新激活突变体 P53 发挥协同抗肿瘤作用。
DOI：
10.1159/000487786
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发表时间：
2018
影响因子：
--
通讯作者：
Zou Lijuan
中科院分区：
文献类型：
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作者：
Li Zongjuan;Xu Xiangdong;Li Yizhuo;Zou Kun;Zhang Zhuo;Xu Xiaoying;Liao Yina;Zhao Xinrui;Jiang Wei;Yu Wendan;Guo Wei;Chen Yiming;Li Yixin;Chen Miao;Deng Wu-Guo;Li Liren;Zou Lijuan
背景/目的PI 3 KCA和突变型p53与肿瘤发生和癌症发展相关。NVP-BKM 120是一种选择性泛PI 3 K抑制剂，通过抑制PI 3 K信号通路发挥抗肿瘤活性。Prima-1 Met是一种低分子量化合物，可以通过恢复其转录功能来拯救突变型p53的功能获得性。在这项研究中，我们调查是否PI 3 K抑制结合突变型p53再激活可以提高甲状腺癌cells的抗肿瘤作用。方法BKM 120和Prima-1 Met对甲状腺癌细胞的增殖，凋亡，迁移和侵袭的影响，分别通过MTT法，集落形成，流式细胞术，伤口愈合和transwell实验。采用RT-PCR和Western blot检测特异性标志物的表达水平，以评估甲状腺分化。结果BKM 120和Prima-1 Met联合治疗显著增强了对甲状腺细胞系中细胞活力、集落形成、迁移和侵袭的抑制以及对细胞凋亡的诱导，并通过抑制PI 3 K/Akt/mTOR和EMT信号通路，上调p53靶基因，并触发细胞色素c的释放。此外，BKM 120和Prima-1 Met的组合通过上调甲状腺特异性分化标志物的表达和抑制癌症干细胞标志物的表达来抑制甲状腺癌细胞的干细胞样特征并促进其分化。此外，机制研究表明，联合处理协同废除了CPSF 4在hTERT启动子处的结合，从而抑制hTERT表达。一致的是，hTERT的过度表达拯救了BKM 120和Prima-1 Met.ConclusionOur结果表明，BKM 120与Prima-1 Met的组合通过抑制PI 3 K/Akt/mTOR和CPSF 4/hTERT信号传导和重新激活突变型p53协同抑制甲状腺癌细胞和肿瘤异种移植物的生长。
Background/AimsPI3KCA and mutant p53 are associated with tumorigenesis and the development of cancers. NVP-BKM120, a selective pan-PI3K inhibitor, exerts the antitumor activity by suppressing the PI3K signaling pathway. Prima-1 Met, a low molecular weight compound, can rescue the gain-of-function of mutant p53 by restoring its transcriptional function. In this study, we investigated whether PI3K inhibition combined with mutant p53 reactivation could enhance the antitumor effect in thyroid cancer cells.MethodsThe effects of BKM120 and Prima-1 Met on the proliferation, apoptosis, migration and invasion of thyroid cancer cells were measured by MTT, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Thyroid differentiation was assessed by detecting the expression levels of specific markers using RT-PCR and Western blot. The in vivo antitumor efficacy was analyzed in a mouse xenograft model.ResultsThe combinational treatment of BKM120 and Prima-1 Met significantly enhanced the inhibitions of cell viability, colony formation, migration and invasion, and the induction of apoptosis in thyroid cell lines, and synergistically suppressed tumor xenograft growth by inhibiting the PI3K/Akt/mTOR and EMT signaling pathways, up-regulating p53 targeted genes, and triggering the release of cytochrome c. Moreover, the combination of BKM120 and Prima-1 Met suppressed the stemlike traits of thyroid cancer cells and promoted their differentiation by upregulating the expression of thyroid-specific differentiation markers and repressing the expression of cancer stem cell markers. Furthermore, the mechanism study demonstrated that the combinational treatment synergistically abrogated the binding of CPSF4 at the promoter of hTERT and thus suppressed hTERT expression. Consistently, overexpression of hTERT rescued the inhibitions of cell viability, invasion and stem-like traits mediated by the combination of BKM120 and Prima-1 Met.ConclusionOur results showed that the combination of BKM120 with Prima-1 Met synergistically suppressed the growth of thyroid cancer cells and tumor xenografts via inhibiting PI3K/Akt/mTOR and CPSF4/hTERT signaling and reactivating mutant p53.