Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer.
The heat shock protein 90 (Hsp90) has a critical role in malignant transformation. Whereas its ability to maintain the functional conformations of mutant and aberrant oncoproteins is established, a transformation-specific regulation of the antiapoptotic phenotype by Hsp90 is poorly understood. By using selective compounds, we have discovered that small-cell lung carcinoma is a distinctive cellular system in which apoptosis is mainly regulated by Hsp90. Unlike the well-characterized antiapoptotic chaperone Hsp70, Hsp90 is not a general inhibitor of apoptosis, but it assumes this role in systems such as small-cell lung carcinoma, in which apoptosis is uniquely dependent on and effected through the intrinsic pathway, without involvement of caspase elements upstream of mitochondria or alternate pathways that are not apoptosome-channeled. These results provide important evidence for a transformation-specific interplay between chaperones in regulating apoptosis in malignant cells.
Rodina
Anna
A
Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Vilenchik
Maria
M
Moulick
Kamalika
K
Aguirre
Julia
J
Kim
Joungnam
J
Chiang
Anne
A
Litz
Julie
J
Clement
Cristina C
CC
Kang
Yanlong
Y
She
Yuhong
Y
Wu
Nian
N
Felts
Sara
S
Wipf
Peter
P
Massague
Joan
J
Jiang
Xuejun
X
Brodsky
Jeffrey L
JL
Krystal
Geoffrey W
GW
Chiosis
Gabriela
G
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008956:Models, Chemical; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D019869:Phosphatidylinositol 3-Kinases