Chaudhari Namrata, Talwar Priti, Lefebvre D'hellencourt Christian, Ravanan Palaniyandi
Apoptosis and Cell Survival Research Lab, Department of Biosciences, School of Biosciences and Technology, VIT University, Vellore, India.
Université de La Réunion, Institut National de la Santé et de la Recherche Médicale, UMR Diabète Athérothombose Thérapies Réunion Océan Indien, Saint-Denis de La Réunion, France.
Front Mol Neurosci. 2017 Sep 26;10:310. doi: 10.3389/fnmol.2017.00310. eCollection 2017.
Neuroblastoma is the most common solid extra cranial tumor in infants. Improving the clinical outcome of children with aggressive tumors undergoing one of the multiple treatment options has been a major concern. Differentiating neuroblastoma cells holds promise in inducing tumor growth arrest and treating minimal residual disease. In this study, we investigated the effect of partial PPARγ agonist 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) on human neuroblastoma IMR32 cells. Our results demonstrate that treatment with low concentration of CDDO and particularly in combination with all trans retinoic acid (ATRA) induced neurite outgrowth, increased the percentage of more than two neurites bearing cells, and decreased viability in IMR32 cells. These morphological changes were associated with an increase in expression of bonafide differentiation markers like β3-tubulin and Neuron Specific Enolase (NSE). The differentiation was accompanied by a decrease in the expression of whose amplification is known to contribute to the pathogenesis of neuroblastoma. MYCN is known to negatively regulate NMYC downstream-regulated gene 1 (NDRG1) in neuroblastomas. down-regulation induced by CDDO correlated with increased expression of NDRG1. CDDO decreased Anaplastic Lymphoma Kinase () mRNA expression without affecting its protein level, while ATRA significantly down-regulated ALK. Antagonism of PPARγ receptor by T0070907 meddled with differentiation inducing effects of CDDO as observed by stunted neurite growth, increased viability and decreased expression of differentiation markers. Our findings indicate that IMR32 differentiation induced by CDDO in combination with ATRA enhances, differentiation followed by cell death via cAMP-response-element binding protein (CREB) independent and PPARγ dependent signaling mechanisms.
神经母细胞瘤是婴儿最常见的颅外实体瘤。改善接受多种治疗方案之一的侵袭性肿瘤患儿的临床结局一直是主要关注点。使神经母细胞瘤细胞分化有望诱导肿瘤生长停滞并治疗微小残留病。在本研究中，我们研究了部分PPARγ激动剂2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸（CDDO）对人神经母细胞瘤IMR32细胞的影响。我们的结果表明，用低浓度的CDDO处理，特别是与全反式维甲酸（ATRA）联合处理，可诱导IMR32细胞出现神经突生长，增加有两条以上神经突的细胞百分比，并降低细胞活力。这些形态学变化与β3-微管蛋白和神经元特异性烯醇化酶（NSE）等真正分化标志物的表达增加有关。分化伴随着 表达的降低，已知其扩增有助于神经母细胞瘤的发病机制。已知MYCN在神经母细胞瘤中负调控NMYC下游调节基因1（NDRG1）。CDDO诱导的 下调与NDRG1表达增加相关。CDDO降低间变性淋巴瘤激酶（）mRNA表达但不影响其蛋白水平，而ATRA显著下调ALK。T0070907对PPARγ受体的拮抗作用干扰了CDDO的分化诱导作用，表现为神经突生长受阻、细胞活力增加和分化标志物表达降低。我们的研究结果表明，CDDO与ATRA联合诱导的IMR32分化通过独立于cAMP反应元件结合蛋白（CREB）和依赖于PPARγ的信号机制增强分化并随后导致细胞死亡。
