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

Hsp105 alpha and Hsp105 beta are major heat shock proteins in mammalian cells that belong to a subgroup of the HSP70 family, HSP105/110. Previously, we have shown that Hsp105 alpha 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 Hsp105 alpha and Hsp105 beta regulate H(2)O(2)-induced apoptosis by using HeLa cells in which expression of Hsp105 alpha or Hsp105 beta was regulated using doxycycline. Overexpression of Hsp105 alpha and Hsp105 beta suppressed the activation of caspase-3 and caspase-9 by preventing the release of cytochrome c from mitochondria in H(2)O(2)-treated cells. Furthermore, both c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) were activated by treatment with H(2)O(2), and the activation of both kinases was suppressed by overexpression of Hsp105 alpha and Hsp105 beta. However, H(2)O(2)-induced apoptosis was suppressed by treatment with a potent inhibitor of p38 MAPK, SB202190, but not a JNK inhibitor, SP600125. These findings suggest that Hsp105 alpha and Hsp105 beta suppress H(2)O(2)-induced apoptosis by suppression of p38 MAPK signaling, one of the essential pathways for apoptosis.