State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
West China School of Basic Sciences and Forensic Medicine, Sichuan University, Chengdu, China.
FASEB J. 2019 Apr;33(4):5520-5534. doi: 10.1096/fj.201801983R. Epub 2019 Jan 22.
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.-Zhou, L., Gao, W., Wang, K., Huang, Z., Zhang, L., Zhang, Z., Zhou, J., Nice, E. C., Huang, C. Brefeldin A inhibits colorectal cancer growth by triggering Bip/Akt-regulated autophagy.
结直肠癌（CRC）是全球最常见的肿瘤疾病之一，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）在体外和体内均具有显著的抗肿瘤活性。诱导完全自噬流被认为是 BFA 诱导的 CRC 抑制的关键事件。在机制上，BFA 引发内质网应激介导的结合免疫球蛋白蛋白（Bip）表达，导致 Bip/Akt 相互作用增加和 Akt 磷酸化减少，从而激活自噬。自噬抑制或 Bip 抑制缓解了 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 抑制中具有协同作用。总之，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。-Zhou, L., Gao, W., Wang, K., Huang, Z., Zhang, L., Zhang, Z., Zhou, J., Nice, E. C., Huang, C. Brefeldin A inhibits colorectal cancer growth by triggering Bip/Akt-regulated autophagy.
