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

Nature Chemical Biology volume 3, pages 498–507 (2007)Cite this article

Abstract

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.

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Figure 1: Cell killing in SCLC cells is a specific result of Hsp90 inhibition.
Figure 2: The PI(3)K-Akt pathway and the intrinsic apoptotic pathway are targets of Hsp90 inhibitor-mediated cell death.
Figure 3: Apoptosis inhibition by Hsp90 is independent of caspases upstream of the mitochondria and is channeled through a caspase-9–caspase-3 pathway.
Figure 4: Mechanism of apoptotic regulation by Hsp90 in SCLC.
Figure 5: Inhibition of apoptosis by Hsp90 is cell- and transformation-specific.
Figure 6: Hsp90 remains the major inhibitor of apoptosis in chemotherapy-resistant SCLC cells.
Figure 7: Pharmacologic inactivation of Hsp90 in in vivo SCLC models results in tumor cell death through apoptosis.

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Acknowledgements

This work was supported by SynCure Cancer Research Foundation (G.C.), Susan G. Komen Breast Cancer Foundation (G.C. and Y.K.), AACR-Cancer Research and Prevention Foundation (G.C.), W.H. Goodwin and A. Goodwin and the Commonwealth Cancer Foundation for Research, The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center (MSKCC) (G.C.), Steps for breath (G.C.), the Translational and Integrative Medicine Research Fund of MSKCC (G.C.), Partnership for Cure and the Goldman Philanthropic Partnerships (J.L.B.), the Tri-institutional Program in Chemical Biology (K.M), and the University of Pittsburgh Combinatorial Chemistry Center (P.W., P50-GM067082). We thank D.M. Turner and S. Werner (University of Pittsburgh) for the preparation of MAL3-101, D. Zatorska and H. He (MSKCC) for the preparation of PU24FCl, PU-H58, PU-H71, 17AAG and 17DMAG, S. Danishefsky (MSKCC, New York) for providing a sample of cycloproparadicicol, the MSKCC Thoracic Service for providing the clinical sample used to establish the SKI-AC3 cell line, and Y. Lazebnik (Cold Spring Harbor Laboratory, New York) and D. Toft (Mayo Clinic) for the generous gifts of antibodies. We thank Y. Lazebnik and N. Rosen for useful discussions in the preparation of this manuscript.

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Author notes

  1. Maria Vilenchik

    Present address: Present address: Hoffmann-La Roche Inc., 500 Kingsland St., Nutley, New Jersey 07110-1046, USA.,

  2. Anna Rodina and Maria Vilenchik: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Anna Rodina, Maria Vilenchik, Kamalika Moulick, Julia Aguirre, Joungnam Kim, Cristina C Clement, Yanlong Kang, Yuhong She, Nian Wu & Gabriela Chiosis

  2. Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Anne Chiang & Joan Massague

  3. Department of Medicine, Medical College of Virginia/Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, 1201 Broad Rock Boulevard, Richmond, 23249, Virginia, USA

    Julie Litz & Geoffrey W Krystal

  4. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street, Rochester, 55905, Minnesota, USA

    Sara Felts

  5. Department of Chemistry, University of Pittsburgh, 274A Crawford Hall, Pittsburgh, 15260, Pennsylvania, USA

    Peter Wipf

  6. Program in Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Xuejun Jiang

  7. Department of Biological Sciences, University of Pittsburgh, 274A Crawford Hall, Pittsburgh, 15260, Pennsylvania, USA

    Jeffrey L Brodsky

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Contributions

A.R., M.V. and C.C.C. designed, performed and analyzed experiments and helped write the paper; K.M., J.A., J.K., A.C., J.L. and Y.K. performed and analyzed experiments; Y.S., S.F. and N.W. designed and analyzed experiments; G.C., X.J., J.M., P.W., G.W.K. and J.L.B. designed and analyzed experiments and helped write the paper.

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Correspondence to Gabriela Chiosis.

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Competing interests

Several compounds disclosed in this presentation have been licensed out to Conforma Therapeutics (currently Biogen Idec). G.C. has received a share of some payments by the licensee. G.C. may receive a share of eventual royalties.

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Rodina, A., Vilenchik, M., Moulick, K. et al. Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol 3, 498–507 (2007). https://doi.org/10.1038/nchembio.2007.10

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