Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 3, pp 433–443

Heat shock protein 90 inhibition abrogates hepatocellular cancer growth through cdc2-mediated G2/M cell cycle arrest and apoptosis

  • Go Watanabe
  • Kevin E. Behrns
  • Jae-Sung Kim
  • Robin D. Kim
Original Article

Abstract

Purpose

17-(demethoxy), 17-allylamino geldanamycin (17-AAG) suppresses growth in some cancers by inhibiting Heat shock protein 90 (Hsp90). We examined the effects of 17-AAG-mediated Hsp90 inhibition on human hepatocellular carcinoma (HCC) growth in vitro and in vivo.

Methods

Human HCC cell lines, Hep3B and HuH7, were exposed to 17-AAG and cell viabilities and apoptosis were determined. Cell cycle profiles were analyzed and the G2/M cell cycle checkpoint proteins cdc2 and cyclin B1 were examined. Studies were performed to determine whether 17-AAG-mediated cdc2 decrease was due to altered gene expression, transcription, or protein degradation. The effects of 17-AAG on Hep3B and HuH7 xenograft growth in athymic nude mice were also examined.

Results

Hep3B and HuH7 treated with 17-AAG versus untreated controls showed decreased cell viability and increased apoptosis. Cells treated with 17-AAG also showed an increased fraction in G2/M phase and an associated decrease in cdc2 through protein degradation rather than through other mechanisms. Hsp90 inhibition by 17-AAG also decreased HCC xenograft growth in association with decreased cdc2 expression.

Conclusions

17-AAG-mediated inhibition of Hsp90 abrogates human HCC cell growth in vitro and in vivo through cdc2 decrease, which in turn induces G2/M cell cycle arrest and apoptosis. Hsp90 is a mediator of HCC growth and survival and its inhibition may serve as a potential treatment.

Keywords

Hepatocellular cancer Hsp90 17-AAG Xenograft cdc2 

Supplementary material

280_2008_888_MOESM1_ESM.tif (8 mb)
Supplementary Figure S1 (TIFF 8233 kb)

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Go Watanabe
    • 1
  • Kevin E. Behrns
    • 1
  • Jae-Sung Kim
    • 1
  • Robin D. Kim
    • 1
  1. 1.Department of SurgeryUniversity of Florida College of MedicineGainesvilleUSA

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