Heat shock protein 90 mediates the apoptosis and autophage in nicotinic-mycoepoxydiene-treated HeLa cells.

Abstract

Heat shock protein 90 (Hsp90) is a fascinating target for cancer therapy due to its significant role in the crossroad of multiple signaling pathways associated with cell proliferation and regulation. Hsp90 inhibitors have the potential to be developed into anti-cancer drugs. Here, we identified nicotinic-mycoepoxydiene (NMD), a structurally novel compound as Hsp90 inhibitor to perform the anti-tumor activity. The compound selectively bound to the Hsp90 N-terminal domain, and degraded the Hsp90 client protein Akt. The degradation of Akt detained Bad in non-phosphorylation form. NMD-associated apoptosis was characterized by the formation of fragmented nuclei, poly(ADP-ribose) polymerase cleavage, cytochrome c release, caspase-3 activation, and the increased proportion of sub-G1 phase cells. Interestingly, the apoptosis was accompanied with autophagy, by exhibiting the increased expression of LC-3 and the decrease of lysosome pH value. Our findings provide a novel cellular mechanism by which Hsp90 inhibitor adjusts cell apoptosis and autophagy in vitro, suggesting that NMD not only has a potential to be developed into a novel anti-tumor pharmaceutical, but also exhibits a new mechanism in regulating cancer cell apoptosis and autophagy via Hsp90 inhibition.

• Authors: Yifei Sun, Shuyan Xiao, Junjie Chen, Miaomiao Wang, Zhonghui Zheng, Siyang Song, Lianru Zhang
• Journal: Acta biochimica et biophysica Sinica (Acta Biochim Biophys Sin (Shanghai)) Vol. 47 Issue 6 Pg. 451-8 (Jun 2015) ISSN: 1745-7270 [Electronic] China
• PMID: 25948110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

Chemical References

• Bridged-Ring Compounds
• HSP90 Heat-Shock Proteins
• Pyrones
• mycoepoxydiene
• Nicotine
• Chloroquine
• Cytochromes c

Topics

• Apoptosis (physiology)
• Autophagy (physiology)
• Bridged-Ring Compounds (chemistry, pharmacology)
• Chloroquine (pharmacology)
• Cytochromes c (metabolism)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, physiology)
• HeLa Cells
• Humans
• Nicotine (chemistry)
• Pyrones (chemistry, pharmacology)
• Signal Transduction