Geldanamycin induces mitotic catastrophe and subsequent apoptosis in human glioma cells.
Geldanamycin (GA) binds to heat shock protein 90 (Hsp90) and interferes with its function which is to protect various cellular proteins involved in signaling, growth control, and survival from ubiquitination and subsequent degradation by the proteasome. Recently, we demonstrated that GA inhibited migration of glioma cells in vitro associated with downregulation of hypoxia-inducible factor (HIF-1 alpha) and phosphorylation of focal adhesion kinase (FAK) (Zagzag et al., 2003, J Cell Physiol 196:394-402). Here, we have investigated the mechanisms through which GA treatment of the T98G glioma cell line induces apoptosis. We found that GA treatment induced cell death in a caspase-dependent manner through activation of caspase-3 and PARP cleavage together with release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria. Use of synchronized T98G cells showed that GA treatment of glioma cells during S-phase enhanced cytotoxicity followed by M-phase arrest, resulting in mitotic catastrophe. In addition, apoptosis was associated with the downregulation of the survival protein, phosphorylated Akt (pAkt), an important signaling protein in the PI3K pathway, that is overexpressed in many cancers including gliomas. Given that many glioma tumors show deregulation of the PI3K signaling pathway, either through loss of the tumor suppressor protein PTEN or overexpression of the growth factor EGFR, the ability to identify different subsets of patients using simple immunohistochemistry for the presence of absence of pAkt could enable selection of the appropriate kinase inhibitor, such as GA, for drug therapy. Based on our data presented here, GA or its analogs may have potential in the treatment of glioma.
Nomura
Motohiro
M
Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, New York 10016, USA.
Nomura
Naoko
N
Newcomb
Elizabeth W
EW
Lukyanov
Yevgeniy
Y
Tamasdan
Cristina
C
Zagzag
David
D
D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor; D016227:Benzoquinones; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005420:Flavoproteins / Q000378:metabolism; D005910:Glioma / Q000473:pathology*; D006801:Humans; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D011809:Quinones / Q000494:pharmacology*
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D016227:Benzoquinones; D005420:Flavoproteins; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D011809:Quinones; D045304:Cytochromes c; C001277:geldanamycin