Suebsoonthron Junjira, Jaroonwitchawan Thiranut, Yamabhai Montarop, Noisa Parinya
Molecular Biotechnology Laboratory, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Ratchasima, Thailand.
Anticancer Drugs. 2017 Jun;28(5):469-479. doi: 10.1097/CAD.0000000000000478.
Neuroblastoma is one of the most common cancers in infancy, arising from the neuroblasts during embryonic development. This cancer is difficult to treat and resistance to chemotherapy is often found; therefore, clinical trials of novel therapeutic approaches, such as targeted-cancer signaling, could be an alternative for a better treatment. WNT signaling plays significant roles in the survival, proliferation, and differentiation of human neuroblastoma. In this report, WNT signaling of a malignant human neuroblastoma cell line, SH-SY5Y cells, was inhibited by XAV939, a specific inhibitor of the Tankyrase enzyme. XAV939 treatment led to the reduction of β-catenin within the cells, confirming its inhibitory effect of WNT. The inhibition of WNT signaling by XAV939 did not affect cell morphology, survival, and proliferation; however, the differentiation and sensitivity to anticancer drugs of human neuroblastoma cells were altered. The treatment of XAV939 resulted in the downregulation of mature neuronal markers, including β-tubulin III, PHOX2A, and PHOX2B, whereas neural progenitor markers (PAX6, TFAP2α, and SLUG) were upregulated. In addition, the combination of XAV939 significantly enhanced the sensitivity of SH-SY5Y and IMR-32 cells to doxorubicin in both 2D and 3D culture systems. Microarray gene expression profiling suggested numbers of candidate target genes of WNT inhibition by XAV939, in particular, p21, p53, ubiquitin C, ZBED8, MDM2, CASP3, and FZD1, and this explained the enhanced sensitivity of SH-SY5Y cells to doxorubicin. Altogether, these results proposed that the altered differentiation of human malignant neuroblastoma cells by inhibiting WNT signaling sensitized the cells to anticancer drugs. This approach could thus serve as an effective treatment option for aggressive brain malignancy.
神经母细胞瘤是婴儿期最常见的癌症之一，起源于胚胎发育过程中的神经母细胞。这种癌症难以治疗，且常出现化疗耐药性；因此，新型治疗方法的临床试验，如靶向癌症信号传导，可能是实现更好治疗效果的一种选择。WNT信号传导在人类神经母细胞瘤的存活、增殖和分化中发挥着重要作用。在本报告中，一种端锚聚合酶特异性抑制剂XAV939抑制了恶性人类神经母细胞瘤细胞系SH-SY5Y细胞的WNT信号传导。XAV939处理导致细胞内β-连环蛋白减少，证实了其对WNT的抑制作用。XAV939对WNT信号传导的抑制不影响细胞形态、存活和增殖；然而，人类神经母细胞瘤细胞的分化和对抗癌药物的敏感性发生了改变。XAV939处理导致成熟神经元标志物（包括β-微管蛋白III、PHOX2A和PHOX2B）下调，而神经祖细胞标志物（PAX6、TFAP2α和SLUG）上调。此外，在二维和三维培养系统中，XAV939的联合使用显著增强了SH-SY5Y和IMR-32细胞对阿霉素的敏感性。基因芯片表达谱分析表明，XAV939抑制WNT有多个候选靶基因，特别是p21、p53、泛素C、ZBED8、MDM2、CASP3和FZD1，这解释了SH-SY5Y细胞对阿霉素敏感性增强的原因。总之，这些结果表明，通过抑制WNT信号传导改变人类恶性神经母细胞瘤细胞的分化，可使细胞对抗癌药物敏感。因此，这种方法可作为侵袭性脑恶性肿瘤的一种有效治疗选择。
