Journal
FASEB JOURNAL
Volume 33, Issue 4, Pages 5520-5534Publisher
WILEY
DOI: 10.1096/fj.201801983R
Keywords
cancer therapy; ER stress; autophagic flux
Categories
Funding
- Chinese National Natural Science Foundation of China (NSFC) [81430071, 81790251, 81672381, 81602194]
- National Key Research and Development Program of China [2016YFC1200203]
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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.
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