Zhen Zijun, Yang Kaibin, Ye Litong, You Zhiyao, Chen Rirong, Liu Ying, He Youjian
State Key Laboratory of Oncology in South China, Guangzhou, China.
Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Cancer Sci. 2017 Jul;108(7):1485-1492. doi: 10.1111/cas.13279. Epub 2017 Jun 19.
Paclitaxel is not as effective for neuroblastoma as most of the front-line chemotherapeutics due to drug resistance. This study explored the regulatory mechanism of paclitaxel-associated autophagy and potential solutions to paclitaxel resistance in neuroblastoma. The formation of autophagic vesicles was detected by scanning transmission electron microscopy and flow cytometry. The autophagy-associated proteins were assessed by western blot. Autophagy was induced and the autophagy-associated proteins LC3-I, LC3-II, Beclin 1, and thioredoxin-related protein 14 (TRP14), were found to be upregulated in neuroblastoma cells that were exposed to paclitaxel. The inhibition of Beclin 1 or TRP14 by siRNA increased the sensitivity of the tumor cells to paclitaxel. In addition, Beclin 1-mediated autophagy was regulated by TRP14. Furthermore, the TRP14 inhibitor suberoylanilide hydroxamic acid (SAHA) downregulated paclitaxel-induced autophagy and enhanced the anticancer effects of paclitaxel in normal control cancer cells but not in cells with upregulated Beclin 1 and TRP14 expression. Our findings showed that paclitaxel-induced autophagy in neuroblastoma cells was regulated by TRP14 and that SAHA could sensitize neuroblastoma cells to paclitaxel by specifically inhibiting TRP14.
由于耐药性，紫杉醇对神经母细胞瘤的疗效不如大多数一线化疗药物。本研究探讨了紫杉醇相关自噬的调控机制以及神经母细胞瘤中紫杉醇耐药的潜在解决方案。通过扫描透射电子显微镜和流式细胞术检测自噬小泡的形成。通过蛋白质免疫印迹法评估自噬相关蛋白。诱导自噬后，发现暴露于紫杉醇的神经母细胞瘤细胞中自噬相关蛋白LC3-I、LC3-II、Beclin 1和硫氧还蛋白相关蛋白14（TRP14）上调。用小干扰RNA（siRNA）抑制Beclin 1或TRP14可增加肿瘤细胞对紫杉醇的敏感性。此外，Beclin 1介导的自噬受TRP14调控。此外，TRP14抑制剂辛二酰苯胺异羟肟酸（SAHA）下调了紫杉醇诱导的自噬，并增强了紫杉醇对正常对照癌细胞的抗癌作用，但对Beclin 1和TRP14表达上调的细胞无效。我们的研究结果表明，神经母细胞瘤细胞中紫杉醇诱导的自噬受TRP14调控，SAHA可通过特异性抑制TRP14使神经母细胞瘤细胞对紫杉醇敏感。
