Apoptosis

, Volume 12, Issue 8, pp 1479–1488 | Cite as

Acute acidification or amiloride treatment suppresses the ability of Hsp70 to inhibit heat-induced apoptosis

  • Guillaume Lachapelle
  • Stefanie M. Radicioni
  • Adam R. Stankiewicz
  • Dick D. Mosser
Original Paper

Abstract

Inhibition of stress-induced apoptosis by the molecular chaperone protein Hsp70 is a contributing factor in tumorigenesis and suppression of this ability could increase the effectiveness of anti-tumor therapy. Tumor cells exist in an acidic environment and acute acidification can sensitize tumor cells to heat-induced cell death. However, the ability of Hsp70 to prevent apoptosis under these conditions has not been examined. The effect of acute acidification on heat-induced apoptosis was examined in a human T-cell line with tetracycline-regulated Hsp70 expression. Apoptosis was inhibited in cells exposed to hyperthermia in acidic media when examined 6 h after the heat stress, but resumed if cells were returned to physiological pH during this recovery period. Long-term proliferation assays showed that acute acidification sensitized cells to heat-induced apoptosis. Hsp70 expressing cells were also sensitized and this was correlated with a reduced ability to suppress the activation of JNK (c-jun N-terminal kinase), Bax and caspase-3. Further sensitization could be achieved with the NHE1 (Na+/H+ exchanger) inhibitor HMA (5-(N, N-hexamethylene) amiloride), which potentiated JNK activation in heat-shocked cells. These results demonstrate that the ability of Hsp70 to suppress apoptosis is compromised when cells are exposed to hyperthermia in an acidic environment, which is correlated with an impaired ability to inhibit JNK activation.

Keywords

Apoptosis Hyperthermia Intracellular acidification Hsp70 JNK Bax 

Notes

Acknowledgements

This work was supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Guillaume Lachapelle
    • 1
  • Stefanie M. Radicioni
    • 1
  • Adam R. Stankiewicz
    • 1
  • Dick D. Mosser
    • 1
  1. 1.Department of Molecular and Cellular BiologyUniversity of GuelphGuelphCanada

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