Heat shock protein 90 inhibitor mycoepoxydiene modulates kinase signaling in cervical cancer cells and inhibits in-vivo tumor growth.

Abstract

Heat shock protein 90 (Hsp90) functions within multiple signaling pathways on the basis of its ability to serve as a chaperone for more than 100 client proteins. Thus, inhibition of Hsp90 alone can trigger numerous pathways. Mycoepoxydiene (MED) can inhibit Hsp90 function and induce apoptosis in cervical cancer cells. However, the antitumor efficacy of MED in vivo is still not clear. We examined the efficacy of MED in a mouse xenograft model to further elucidate HeLa cell fate and also assessed the mechanism of altered protein signaling in response to this compound in vitro. Our data showed that Hsp90 inhibition simultaneously triggers signaling that regulates both cell death and cell proliferation, and that HeLa cell death may be a result of the disequilibrium of these signals. MED induces cell death as a result of the destabilization of Akt and IKK, which may promote cell death through a reduction in the activation of Bad and nuclear factor-κB. However, MED also induces the MEK/ERK pathway, which is classically considered to promote cell survival. MEK/ERK activation leads to an increase in p21, a cyclin-dependent kinase inhibitor, and is independent of Raf, but is shown to be mediated by p53. MED also leads to a decrease in several additional G2/M regulatory proteins independent of the MEK/ERK pathway. These results indicate an interesting mechanism of cross-talk between the inhibition of Akt phosphorylation and the activation of the MEK pathway by MED and provide in-vivo evidence for the potential of inhibiting Hsp90 as a candidate anticancer treatment.

• Authors: Peng Lin, Yuting Yi, Mingke Lu, Miaomiao Wang, Yang Yang, Yue Lu, Siyang Song, Zhonghui Zheng, Xianming Deng, Lianru Zhang
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 26 Issue 1 Pg. 25-34 (Jan 2015) ISSN: 1473-5741 [Electronic] England
• PMID: 25014191 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Bridged-Ring Compounds
• HSP90 Heat-Shock Proteins
• Pyrones
• Tumor Suppressor Protein p53
• mycoepoxydiene
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase Kinases

Topics

• Animals
• Antineoplastic Agents (metabolism, pharmacology, therapeutic use)
• Bridged-Ring Compounds (metabolism, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Heterografts
• Humans
• MAP Kinase Kinase Kinases (metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrones (metabolism, pharmacology, therapeutic use)
• Signal Transduction
• Tumor Suppressor Protein p53 (metabolism)
• Uterine Cervical Neoplasms (drug therapy, pathology)