Gao Mingjun, Yang Jin, Gong Hailong, Lin Yuancai, Liu Jing
Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.
Front Pharmacol. 2021 Oct 21;12:760055. doi: 10.3389/fphar.2021.760055. eCollection 2021.
Gliomas are primary tumors originating from glial progenitor cells. Traditional treatments, including surgery, radiotherapy, and chemotherapy, have many limitations concerning the prognosis of patients with gliomas. Therefore, it is important to find novel drugs to effectively treat gliomas. Trametinib has been shown to inhibit the MAPK pathway and regulate its downstream extracellular-related kinases. It has widely been used in the treatment of BRAF V600E mutant metastatic melanomas. Previous studies found that trametinib can improve the prognosis of patients with melanoma brain metastases. In this study, we investigated the therapeutic effects of trametinib on gliomas and . We found that trametinib can inhibit proliferation, migration, and invasion of glioma cells, while inducing apoptosis of glioma cells. Specifically, trametinib can suppress both the expression of in glioma cells and the transport of PKM2 into the cellular nucleus via suppression of expression. However, inhibition of these cellular effects and intracellular glycolysis levels were reversed by overexpressing in glioma cells. We also found inhibition of c-myc with trametinib treatment, but its expression could be increased by overexpressing . Interestingly, when was overexpressed but silenced, we found that the initial inhibition of cellular effects and glycolysis levels by trametinib were once again restored. These inhibitory effects were also confirmed : trametinib inhibited the growth of the transplanted glioma cell tumor, whereas overexpression and silencing restored the inhibition of trametinib on the growth of the transplanted tumor. In conclusion, these experimental results showed that trametinib may inhibit the growth and intracellular glycolysis of glioma cells by targeting the PKM2/c-myc pathway.
胶质瘤是起源于神经胶质祖细胞的原发性肿瘤。传统治疗方法，包括手术、放疗和化疗，在胶质瘤患者的预后方面存在许多局限性。因此，寻找有效治疗胶质瘤的新型药物很重要。曲美替尼已被证明可抑制丝裂原活化蛋白激酶（MAPK）通路并调节其下游细胞外相关激酶。它已广泛用于治疗BRAF V600E突变转移性黑色素瘤。先前的研究发现曲美替尼可改善黑色素瘤脑转移患者的预后。在本研究中，我们研究了曲美替尼对胶质瘤的治疗效果。我们发现曲美替尼可抑制胶质瘤细胞的增殖、迁移和侵袭，同时诱导胶质瘤细胞凋亡。具体而言，曲美替尼可通过抑制胶质瘤细胞中 的表达以及抑制PKM2转运至细胞核来抑制 的表达。然而，在胶质瘤细胞中过表达 可逆转这些细胞效应和细胞内糖酵解水平的抑制。我们还发现曲美替尼治疗可抑制c-myc，但过表达 可增加其表达。有趣的是，当过表达 但沉默 时，我们发现曲美替尼对细胞效应和糖酵解水平的初始抑制作用再次恢复。这些抑制作用也得到了证实：曲美替尼抑制移植的胶质瘤细胞肿瘤生长，而过表达 和沉默 可恢复曲美替尼对移植肿瘤生长的抑制作用。总之，这些实验结果表明，曲美替尼可能通过靶向PKM2/c-myc通路抑制胶质瘤细胞的生长和细胞内糖酵解。
