Mammalian 105 kDa heat shock family proteins suppress hydrogen peroxide-induced apoptosis through a p38 MAPK-dependent mitochondrial pathway in HeLa cells

Hsp105α and Hsp105β are major heat shock proteins in mammalian cells that belong to a subgroup of the HSP70 family, HSP105/110. Previously, we have shown that Hsp105α has opposite effects on stress-induced apoptosis depending on the cell type. However, it is not fully understood how Hsp105 regulates stress-induced apoptosis. In this study, we examined how Hsp105α and Hsp105β regulate H₂O₂-induced apoptosis by using HeLa cells in which expression of Hsp105α or Hsp105β was regulated using doxycycline. Overexpression of Hsp105α and Hsp105β suppressed the activation of caspase-3 and caspase-9 by preventing the release of cytochrome c from mitochondria in H₂O₂-treated cells. Furthermore, both c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) were activated by treatment with H₂O₂, and the activation of both kinases was suppressed by overexpression of Hsp105α and Hsp105β. However, H₂O₂-induced apoptosis was suppressed by treatment with a potent inhibitor of p38 MAPK, SB202190, but not a JNK inhibitor, SP600125. These findings suggest that Hsp105α and Hsp105β suppress H₂O₂-induced apoptosis by suppression of p38 MAPK signaling, one of the essential pathways for apoptosis.