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Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization.

鱼藤素通过抑制 EGFR 信号通路和促进 gsk3 β/FBW7-mediated 的失稳抑制非小细胞肺癌 Mcl-1。

  • 影响因子:5.9590
  • DOI:10.1038/s41419-020-2344-0
  • 作者列表:"Gao F","Yu X","Li M","Zhou L","Liu W","Li W","Liu H
  • 发表时间:2020-02-21
Abstract

:Activating mutations of epidermal growth factor receptor (EGFR) play crucial roles in the oncogenesis of human non-small cell lung cancer (NSCLC). By screening 79 commercially available natural products, we found that the natural compound deguelin exhibited a profound anti-tumor effect on NSCLC via directly down-regulating of EGFR-signaling pathway. Deguelin potently inhibited in vitro EGFR kinase activity of wild type (WT), exon 19 deletion, and L858R/T790M-mutated EGFR. The in silico docking study indicated that deguelin was docked into the ATP-binding pocket of EGFRs. By suppression of EGFR signaling, deguelin inhibited anchorage-dependent, and independent growth of NSCLC cell lines, and significantly delayed tumorigenesis in vivo. Further study showed that deguelin inhibited EGFR and downstream kinase Akt, which resulted in the activation of GSK3β and eventually enhanced Mcl-1 phosphorylation at S159. Moreover, deguelin promoted the interaction between Mcl-1 and E3 ligase SCFFBW7, which enhanced FBW7-mediated Mcl-1 ubiquitination and degradation. Additionally, phosphorylation of Mcl-1 by GSK3β is a prerequisite for FBW7-mediated Mcl-1 destruction. Depletion or pharmacological inactivation of GSK3β compromised deguelin-induced Mcl-1 ubiquitination and reduction. Taken together, our data indicate that enhancement of ubiquitination-dependent Mcl-1 turnover might be a promising approach for cancer treatment.

摘要

表皮生长因子受体 (EGFR) 的激活突变在人类非小细胞肺癌 (NSCLC) 的肿瘤发生中起着至关重要的作用。通过筛选 79 种市售天然产物,我们发现天然化合物鱼藤素通过直接下调 EGFR 信号通路对 NSCLC 表现出深刻的抗肿瘤作用。Deguelin 在体外强效抑制野生型 (WT) 、外显子 19 缺失和 L858R/T790M-mutated EGFR 激酶活性。计算机对接研究表明鱼藤素被对接到 EGFRs 的 ATP 结合口袋中。通过抑制 EGFR 信号,鱼藤素抑制 NSCLC 细胞系的锚定依赖性和非依赖性生长,并显著延缓体内肿瘤发生。进一步研究表明,鱼藤素抑制 EGFR 和下游激酶 Akt,从而导致 gsk3 β 的活化,最终增强 s159 的 Mcl-1 磷酸化。此外,鱼藤素促进 Mcl-1 与 E3 连接酶 SCFFBW7 之间的相互作用,从而增强 FBW7-mediated 泛素化和降解 Mcl-1。此外,gsk3 β 磷酸化 Mcl-1 是 FBW7-mediated 破坏 Mcl-1 先决条件。Gsk3 β 受损的鱼藤素的耗竭或药理学失活诱导的 Mcl-1 泛素化和还原。总之,我们的数据表明,增强泛素化依赖性 Mcl-1 转换可能是一种很有前途的癌症治疗方法。

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影响因子:1.84
发表时间:2020-01-01
来源期刊:Oncology letters
DOI:10.3892/ol.2019.11149
作者列表:["Das SK","Huang YY","Li B","Yu XX","Xiao RH","Yang HF"]

METHODS::The aim of the present study was to compare the safety and efficacy of cryoablation (CA) and microwave ablation (MWA) as treatments for non-small cell lung cancer (NSCLC). Patients with stage IIIB or IV NSCLC treated with CA (n=45) or MWA (n=56) were enrolled in the present study. The primary endpoint was progression-free survival (PFS); the secondary endpoints included overall survival (OS) time and adverse events (AEs). The median PFS times between the two groups were not significantly different (P=0.36): CA, 10 months [95% confidence interval (CI), 7.5-12.4] vs. MWA, 11 months (95% CI, 9.5-12.4). The OS times between the two groups were also not significantly different (P=0.07): CA, 27.5 months (95% CI, 22.8-31.2 months) vs. MWA, 18 months (95% CI, 12.5-23.5). For larger tumors (>3 cm), patients treated with MWA had significantly longer median PFS (P=0.04; MWA, 10.5 months vs. CA, 7.0 months) and OS times (P=0.04; MWA, 24.5 months vs. CA, 14.5 months) compared patients treated with CA. However, for smaller tumors (≤3 cm), median PFS (P=0.79; MWA, 11.0 months vs. CA, 13.0 months) and OS times (P=0.39; MWA, 30.0 months vs. CA, 26.5 months) between the two groups did not differ significantly. The incidence rates of AEs were similar in the two groups (P>0.05). The number of applicators, tumor size and length of the lung traversed by applicators were associated with a higher risk of pneumothorax and intra-pulmonary hemorrhage in the two groups. Treatment with CA resulted in significantly less intraprocedural pain compared with treatment with MWA (P=0.001). Overall, the present study demonstrated that CA and MWA were comparably safe and effective procedures for the treatment of small tumors. However, treatment with MWA was superior compared with CA for the treatment of large tumors.

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发表时间:2020-02-01
DOI:10.1016/j.annonc.2019.10.022
作者列表:["Mazieres J","Cropet C","Montané L","Barlesi F","Souquet PJ","Quantin X","Dubos-Arvis C","Otto J","Favier L","Avrillon V","Cadranel J","Moro-Sibilot D","Monnet I","Westeel V","Le Treut J","Brain E","Trédaniel J","Jaffro M","Collot S","Ferretti GR","Tiffon C","Mahier-Ait Oukhatar C","Blay JY"]

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