High levels of heat shock protein Hsp72 in cancer cells suppress default senescence pathways.
The major heat shock protein Hsp72 is constitutively expressed in many tumor cell lines and biopsies, and its expression correlates with poor prognosis in several types of cancer. Hsp72 was suggested to play an important role in neoplastic transformation and tumor development. We addressed the role of Hsp72 in cancer cells by investigating the consequences of specific depletion of Hsp72 using small interfering RNA. Down-regulation of Hsp72 in certain cancer lines triggered cell senescence associated with activation and stabilization of p53 and induction of the cell cycle inhibitor p21. Effects of Hsp72 depletion on senescence and p53 did not result from a proteotoxic stress, DNA instability, or activation of ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related pathways. Instead, depletion of Hsp72 reduced stability and activity of the p53 inhibitor Hdm2. In addition, Hsp72 depletion triggered a p53-independent senescence program through inhibitory phosphorylation and down-regulation of the cell cycle kinase Cdc2. Therefore, Hsp72 provides a selective advantage to cancer cells by suppressing default senescence via p53-dependent and p53-independent pathways.
Yaglom
Julia A
JA
Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
Gabai
Vladimir L
VL
Sherman
Michael Y
MY
D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D045325:HCT116 Cells; D050884:HSP72 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D020543:Proteome / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D050884:HSP72 Heat-Shock Proteins; D020543:Proteome; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2