Thomaz Amanda, Pinheiro Kelly de Vargas, Souza Bárbara Kunzler, Gregianin Lauro, Brunetto Algemir L, Brunetto André T, de Farias Caroline Brunetto, Jaeger Mariane da Cunha, Ramaswamy Vijay, Nör Carolina, Taylor Michael D, Roesler Rafael
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Front Pharmacol. 2019 Jun 26;10:698. doi: 10.3389/fphar.2019.00698. eCollection 2019.
Neurotrophins are critically involved in regulating normal neural development and plasticity. Brain-derived neurotrophic factor (BDNF), a neurotrophin that acts by binding to the tropomyosin receptor kinase B (TrkB) receptor, has also been implicated in the progression of several types of cancer. However, its role in medulloblastoma (MB), the most common type of malignant brain tumor afflicting children, remains unclear. Here we show that selective TrkB inhibition with the small molecule compound ANA-12 impaired proliferation and viability of human UW228 and D283 MB cells, and slowed the growth of MB tumors xenografted into nude mice. These effects were accompanied by increased apoptosis, reduced extracellular-regulated kinase (ERK) activity, increased expression of signal transducer and activator of transcription 3 (STAT3), and differential modulation of p21 expression dependent on the cell line. In addition, MB cells treated with ANA-12 showed morphological alterations consistent with differentiation, increased levels of the neural differentiation marker β-III Tubulin (TUBB3), and reduced expression of the stemness marker Nestin. These findings are consistent with the possibility that selective TrkB inhibition can display consistent anticancer effects in MB, possibly by modulating intracellular signaling and gene expression related to tumor progression, apoptosis, and differentiation.
神经营养因子在调节正常神经发育和可塑性方面起着关键作用。脑源性神经营养因子（BDNF）是一种通过与原肌球蛋白受体激酶B（TrkB）受体结合而起作用的神经营养因子，也与几种类型癌症的进展有关。然而，其在髓母细胞瘤（MB）（一种折磨儿童的最常见恶性脑肿瘤类型）中的作用仍不清楚。在此，我们表明，用小分子化合物ANA - 12选择性抑制TrkB会损害人UW228和D283 MB细胞的增殖和活力，并减缓移植到裸鼠体内的MB肿瘤的生长。这些效应伴随着细胞凋亡增加、细胞外调节激酶（ERK）活性降低、信号转导和转录激活因子3（STAT3）表达增加以及依赖于细胞系的p21表达的差异调节。此外，用ANA - 12处理过的MB细胞显示出与分化一致的形态学改变、神经分化标志物β - III微管蛋白（TUBB3）水平增加以及干性标志物巢蛋白（Nestin）表达降低。这些发现与以下可能性一致，即选择性抑制TrkB可能通过调节与肿瘤进展、细胞凋亡和分化相关的细胞内信号传导和基因表达，在MB中发挥一致的抗癌作用。
