Article abstract

Nature Chemical Biology 3, 498 - 507 (2007)
Published online: 1 July 2007 | doi:10.1038/nchembio.2007.10

Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer

Anna Rodina1,9, Maria Vilenchik1,8,9, Kamalika Moulick1, Julia Aguirre1, Joungnam Kim1, Anne Chiang2, Julie Litz3, Cristina C Clement1, Yanlong Kang1, Yuhong She1, Nian Wu1, Sara Felts4, Peter Wipf5, Joan Massague2, Xuejun Jiang6, Jeffrey L Brodsky7, Geoffrey W Krystal3 & Gabriela Chiosis1

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.

Top
  1. Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
  2. Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
  3. Department of Medicine, Medical College of Virginia/Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia 23249, USA.
  4. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street, Rochester, Minnesota 55905, USA.
  5. Department of Chemistry, University of Pittsburgh, 274A Crawford Hall, Pittsburgh, Pennsylvania 15260, USA.
  6. Program in Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
  7. Department of Biological Sciences, University of Pittsburgh, 274A Crawford Hall, Pittsburgh, Pennsylvania 15260, USA.
  8. Present address: Hoffmann-La Roche Inc., 500 Kingsland St., Nutley, New Jersey 07110-1046, USA.
  9. These authors contributed equally to this work.

Correspondence to: Gabriela Chiosis1 e-mail: chiosisg@mskcc.org