ZFIN ID: ZDB-PUB-170720-8
The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis
Gaoxiang, W., Pan, Z., Xing, C., Zhao, L., Jiaqi, T., Yang, Y., Fang, Y., Zhou, J.
Date: 2017
Source: Cancer biology & therapy   18(8): 584-595 (Journal)
Registered Authors: Zhou, Jianfeng
Keywords: antitumor, apoptosis, autophagy, elaiophylin, endoplasmic reticulum stress, multiple myeloma, xenograft model
MeSH Terms:
  • Animals
  • Antineoplastic Agents/pharmacology*
  • Antineoplastic Agents/therapeutic use
  • Apoptosis/drug effects*
  • Autophagy/drug effects*
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Endoplasmic Reticulum Stress/drug effects*
  • Female
  • Humans
  • Macrolides/pharmacology*
  • Macrolides/therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Multiple Myeloma/drug therapy*
  • Multiple Myeloma/genetics
  • Mutation
  • Signal Transduction
  • Taurochenodeoxycholic Acid/pharmacology
  • Tumor Suppressor Protein p53/genetics*
  • Xenograft Model Antitumor Assays
  • Zebrafish
PubMed: 28718729 Full text @ Cancer Biol. Ther.
FIGURES
ABSTRACT
Elaiophylin is a natural compound and a novel and potent inhibitor of late stage autophagy with outstanding antitumor activity in human ovarian cancer cells. However, the possible biological effects and functional linkage between elaiophylin and multiple myeloma (MM) have not been explored. This study aimed to assess the effect of elaiophylin on MM cells with mutant TP53 and the possible molecular mechanism. The results suggested that elaiophylin exerted anti-myeloma activity by inducing apoptosis and proliferation arrest. As expected, elaiophylin blocked autophagy flux in MM cells. Subsequently, persistent activation of endoplasmic reticulum (ER) stress was induced. Moreover, the apoptotic effect was to some extent attenuated by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Further studies indicated that elaiophylin effectively suppressed MM cell growth without obvious side effects in zebrafish embryo and mouse xenograft models. Taken together, our data are the first to demonstrate that exposure of human MM cells with mutant TP53 to elaiophylin blocked autophagy flux and thus induced cell death, which partially involved ER stress-associated apoptosis. Targeted disruption of the cellular protein handling system by elaiophylin is therefore a promising therapeutic strategy for overcoming incurable MM, even when TP53 mutations are present.
ADDITIONAL INFORMATION