α-Mangostin suppresses the de novo lipogenesis and enhances the chemotherapeutic response to gemcitabine in gallbladder carcinoma cells via targeting the AMPK/SREBP1 cascades
α-Mangostin suppresses the de novo lipogenesis and enhances the chemotherapeutic response to gemcitabine in gallbladder carcinoma cells via targeting the AMPK/SREBP1 cascades
复制标题
α-山竹素通过靶向 AMPK/SREBP1 级联抑制胆囊癌细胞中的从头脂肪生成并增强对吉西他滨的化疗反应
DOI：
10.1111/jcmm.14785
复制
发表时间：
2019-11-25
影响因子：
5.3
通讯作者：
Dong, Danfeng
中科院分区：
文献类型：
--
作者：
Shi, Yu;Fan, Yangwei;Dong, Danfeng
在某些类型的肿瘤中发现了高速率的从头脂质合成，包括胆囊癌（GBC）。与其他几种肿瘤不同，GBC对标准辅助治疗高度不敏感，这使得其治疗更具挑战性。虽然已经揭示了GBC化疗耐药的几个潜在靶点和信号通路，但确切的机制仍然难以理解。在本研究中，我们发现α-芒果苷，作为一种膳食吨酮，抑制胆囊癌细胞的增殖和克隆形成能力，诱导细胞周期阻滞和凋亡，并抑制从头脂肪生成。潜在的机制可能涉及AMPK的激活，因此，抑制SREBP 1核转位，以钝从头脂肪生成。此外，通过siRNA或α-倒捻子素沉默SREBP 1增强了胆囊癌细胞中吉西他滨的敏感性。体内研究还显示，MA或吉西他滨给药携带NOZ肿瘤的裸鼠可以减少肿瘤生长，此外，MA给药可以显着增强吉西他滨诱导的肿瘤生长抑制。与体外研究结果相一致，MA或吉西他滨单独处理的小鼠肿瘤显示出增殖水平降低，Ki-67表达降低，凋亡增加，TUNEL染色证实，并且MA联合吉西他滨处理组中观察到明显的增殖抑制和凋亡上调。因此，通过MA靶向AMPK/SREBP 1信号传导抑制从头脂肪生成可能为GBC细胞对化疗敏感的潜在策略提供见解。
High rates of de novo lipid synthesis have been discovered in certain kinds of tumours, including gallbladder cancer (GBC). Unlike several other tumours, GBC is highly insensitive to standard adjuvant therapy, which makes its treatment even more challenging. Although several potential targets and signalling pathways underlying GBC chemoresistance have been revealed, the precise mechanisms are still elusive. In this study, we found that alpha-Mangostin, as a dietary xanthone, repressed the proliferation and clone formation ability, induced cell cycle arrest and the apoptosis, and suppressed de novo lipogenesis of gallbladder cancer cells. The underlying mechanisms might involve the activation of AMPK and, therefore, the suppression of SREBP1 nuclear translocation to blunt de novo lipogenesis. Furthermore, SREBP1 silencing by siRNA or alpha-mangostin enhanced the sensitivity of gemcitabine in gallbladder cancer cells. In vivo studies also displayed that MA or gemcitabine administration to nude mice harbouring NOZ tumours can reduce tumour growth, and moreover, MA administration can significantly potentiate gemcitabine-induced inhibition of tumour growth. Corroborating in vitro findings, tumours from mice treated with MA or gemcitabine alone showed decreased levels of proliferation with reduced Ki-67 expression and elevated apoptosis confirmed by TUNEL staining, furthermore, the proliferation inhibition and apoptosis up-regulation were obviously observed in MA combined with gemcitabine treatment group. Therefore, inhibiting de novo lipogenesis via targeting the AMPK/SREBP1 signalling by MA might provide insights into a potential strategy for sensitizing GBC cells to chemotherapy.