Brefeldin A inhibits colorectal cancer growth by triggering Bip/Akt-regulated autophagy
Brefeldin A inhibits colorectal cancer growth by triggering Bip/Akt-regulated autophagy
复制标题
Brefeldin A 通过触发 Bip/Akt 调节的自噬抑制结直肠癌生长
DOI：
10.1096/fj.201801983r
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发表时间：
2019-04-01
期刊：
影响因子：
4.8
通讯作者：
Huang, Canhua
中科院分区：
文献类型：
--
作者：
Zhou, Li;Gao, Wei;Huang, Canhua
结直肠癌（CRC）是世界范围内最常见的肿瘤性疾病之一，有效的治疗仍然是一个挑战。在这里，我们发现大环内酯类抗生素布雷菲德菌素A（BFA）在体外和体内都表现出相当大的抗肿瘤活性。诱导完全自噬通量的特征在于作为一个关键事件在BFA诱导的CRC抑制。从机制上讲，BFA引起内质网应激介导的结合免疫球蛋白（Bip）表达，导致Bip/Akt相互作用增加，导致Akt磷酸化降低，从而激活自噬。自噬抑制或Bip抑制缓解BFA诱导的细胞死亡，表明Bip调节的自噬在BFA的抗肿瘤特性中起关键作用。此外，BFA与紫杉醇或5-氟尿嘧啶在CRC抑制中协同作用。总的来说，我们的研究为BFA诱导的自噬提供了重要的分子基础，并表明抗生素BFA可以重新定位为CRC治疗的潜在抗癌药物。
Colorectal cancer (CRC) is one of the most prevalent neoplastic diseases worldwide, and effective treatment remains a challenge. Here, we found that the macrolide antibiotic brefeldin A (BFA) exhibits considerable antitumor activity both in vitro and in vivo. Induction of complete autophagic flux is characterized as a key event in BFA-induced CRC suppression. Mechanistically, BFA provokes endoplasmic reticulum stress-mediated binding immunoglobulin protein (Bip) expression, leading to increased Bip/Akt interaction and resultant decreased Akt phosphorylation, thereby activating autophagy. Autophagy inhibition or Bip suppression relieves BFA-induced cell death, suggesting a key role for Bip-regulated autophagy in the antitumor properties of BFA. Moreover, BFA acts synergistically with paclitaxel or 5-fluorouracil in CRC suppression. Collectively, our study provides an important molecular basis for BFA-induced autophagy and suggests that the antibiotic BFA could be repositioned as a potential anticancer drug for CRC treatment.