Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
Howard University, Dixon Building, Room 210, 600 W. Street NW, Washington, DC, 20059, USA.
Cell Oncol (Dordr). 2019 Jun;42(3):369-380. doi: 10.1007/s13402-019-00432-4. Epub 2019 Feb 20.
Hepatocellular carcinoma (HCC) is an aggressive malignancy. In HCC, mitogen-activated protein kinase (MAPK) signaling is overactivated. The MAPK kinase (MEK) inhibitor trametinib has been approved to treat several types of advanced cancers with a BRAF mutation. Herein, we examined whether trametinib has efficacy against HCC.
The effects of trametinib on cell viability, proliferation and tumor growth were assessed in HCC-derived cell lines and mouse xenograft models. Western blot analysis and immunohistochemistry were used to identify key regulators critical for HHC cell proliferation and tumor growth.
We found that trametinib dose-dependently inhibited the viability and proliferation of HCC cells. We also found that a strong suppression of MEK by trametinib downregulated the pro-survival protein MYC, but upregulated the pro-apoptotic protein BIM. This dual differential regulation of MYC and BIM was found to be accompanied by upregulation of a MYC-targeted cyclin dependent kinase inhibitor, p27 (p27), and an apoptosis marker, cleaved poly (ADP ribose) polymerase 1 (PARP), indicating a concurrent modulation of cell cycle- and apoptosis-related pathways. Importantly, we found that MYC overexpression did not block increased BIM in trametinib-treated HCC cells, indicating that MAPK signaling independently regulates MYC and BIM. Finally, we found that trametinib in vivo inhibited HepG2 xenograft tumor growth and attenuated tumor invasion into surrounding tissues. Consistent with the in vitro findings, MYC expression was found to be reduced, while p27 expression was found to be elevated, and BIM expression and cleaved PARP levels were found to be increased in trametinib-treated xenograft tumors.
Collectively, our data indicate that trametinib exhibits efficacy in treating HCC cells via distinct regulation of the MYC and BIM pathways. As such, targeting MEK to block MAPK signaling with trametinib may provide novel treatment opportunities for HCC.
肝细胞癌（HCC）是一种侵袭性恶性肿瘤。在 HCC 中，丝裂原活化蛋白激酶（MAPK）信号过度激活。MAPK 激酶（MEK）抑制剂曲美替尼已被批准用于治疗具有 BRAF 突变的几种类型的晚期癌症。在此，我们研究了曲美替尼是否对 HCC 有效。
在 HCC 来源的细胞系和小鼠异种移植模型中评估了曲美替尼对细胞活力、增殖和肿瘤生长的影响。使用 Western blot 分析和免疫组织化学来鉴定对 HCC 细胞增殖和肿瘤生长至关重要的关键调节剂。
我们发现曲美替尼呈剂量依赖性地抑制 HCC 细胞的活力和增殖。我们还发现，曲美替尼对 MEK 的强烈抑制下调了促生存蛋白 MYC，但上调了促凋亡蛋白 BIM。这种对 MYC 和 BIM 的双重差异调节伴随着 MYC 靶向细胞周期依赖性激酶抑制剂 p27（p27）和凋亡标志物 cleaved poly（ADP ribose）polymerase 1（PARP）的上调，表明细胞周期和凋亡相关途径的同时调节。重要的是，我们发现 MYC 过表达不能阻止曲美替尼处理的 HCC 细胞中 BIM 的增加，表明 MAPK 信号独立调节 MYC 和 BIM。最后，我们发现曲美替尼在体内抑制 HepG2 异种移植肿瘤的生长并减弱肿瘤向周围组织的侵袭。与体外发现一致，在曲美替尼处理的异种移植肿瘤中发现 MYC 表达降低，而 p27 表达升高，BIM 表达和 cleaved PARP 水平升高。
总的来说，我们的数据表明，曲美替尼通过对 MYC 和 BIM 途径的不同调节在治疗 HCC 细胞方面显示出疗效。因此，用曲美替尼靶向 MEK 阻断 MAPK 信号可能为 HCC 提供新的治疗机会。
