Radicicol potentiates heat-induced cell killing in a human oesophageal cancer cell line: the Hsp90 chaperone complex as a new molecular target for enhancement of thermosensitivity.
OBJECTIVE
To examine the ability of a heat shock protein 90 (Hsp90) chaperone complex inhibitor, radicicol, to modify thermal response and heat-induced cell killing, and to clarify the underlining mechanisms.


METHODS
A human oesophageal cancer cell line (TE-1), with a mutant p53 gene, was used. To examine the effect of radicicol on heat-induced cell killing, radicicol at a concentration of 100 nM was incubated with the cells for 7 h during heat treatment. Changes in the expression of proteins were examined by Western blot and immunofluorescence analysis.


RESULTS
Radicicol in combination with heat synergistically potentiated heat-induced cellular killing despite an increase in the expression of Hsp72 and Hsp27 caused by radicicol. Heat alone activated Raf-1 and p42/p44 extracellular signal-regulated kinase (Erk), and heat in combination with radicicol inhibited the activation of Raf-1 and p42/p44 Erk through reduced binding of Raf-1 to Hsp90. Phosphorylation of Akt was also decreased by radicicol.


CONCLUSIONS
The Hsp90 chaperone complex inhibitor, radicicol, potentiated heat-induced cellular killing, and inhibition of p42/p44 Erk and Akt activation rather than modification of Hsp expression might be involved in enhancing cellular thermosensitivity. Results suggest that the Hsp90 chaperone complex could be a new molecular target for the modification of the cellular response to heat.
Akimoto
T
T
Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. takimoto@showa.gunma-u.ac.jp
Nonaka
T
T
Harashima
K
K
Sakurai
H
H
Ishikawa
H
H
Mitsuhashi
N
N
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000473:pathology / Q000628:therapy*; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D000076249:Heat Shock Transcription Factors; D006358:Hot Temperature / Q000627:therapeutic use*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D007783:Lactones; D018942:Macrolides; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; C035359:monorden