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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References
Workman, P. & Maloney, A. HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin. Biol. Ther. 2, 3–24 (2002).
Neckers, L. Chaperoning oncogenes: Hsp90 as a target of geldanamycin. Handb. Exp. Pharmacol. 172, 259–277 (2006).
Chiosis, G. Targeting chaperones in transformed systems—a focus on Hsp90 and cancer. Expert Opin. Ther. Targets 10, 37–50 (2006).
Whitesell, L. & Lindquist, S.L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761–772 (2005).
Ciombor, K.K. & Rocha Lima, C.M. Management of small cell lung cancer. Curr. Treat. Options Oncol. 7, 59–68 (2006).
Shivapurkar, N., Reddy, J., Chaudhary, P.M. & Gazdar, A.F. Apoptosis and lung cancer: a review. J. Cell. Biochem. 88, 885–898 (2003).
Joseph, B., Ekedahl, J., Sirzen, F., Lewensohn, R. & Zhivotovsky, B. Differences in expression of pro-caspases in small cell and non-small cell lung carcinoma. Biochem. Biophys. Res. Commun. 262, 381–387 (1999).
Onganer, P.U., Seckl, M.J. & Djamgoz, M.B. Neuronal characteristics of small-cell lung cancer. Br. J. Cancer 93, 1197–1201 (2005).
Salgia, R. & Skarin, A.T. Molecular abnormalities in lung cancer. J. Clin. Oncol. 16, 1207–1217 (1998).
Chau, B.N. & Wang, J.Y. Coordinated regulation of life and death by RB. Nat. Rev. Cancer 3, 130–138 (2003).
Krystal, G.W., Sulanke, G. & Litz, J. Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes apoptosis, and enhances sensitivity of small cell lung cancer cells to chemotherapy. Mol. Cancer Ther. 1, 913–922 (2002).
Tsurutani, J., West, K.A., Sayyah, J., Gills, J.J. & Dennis, P.A. Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy. Cancer Res. 65, 8423–8432 (2005).
Kelland, L.R., Sharp, S.Y., Rogers, P.M., Myers, T.G. & Workman, P. DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J. Natl. Cancer Inst. 91, 1940–1949 (1999).
Cysyk, R.L. et al. Reaction of geldanamycin and C17-substituted analogues with glutathione: product identifications and pharmacological implications. Chem. Res. Toxicol. 19, 376–381 (2006).
Chiosis, G. Discovery and development of purine-scaffold Hsp90 inhibitors. Curr. Top. Med. Chem. 6, 1183–1191 (2006).
Vilenchik, M. et al. Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem. Biol. 11, 787–797 (2004).
Llauger, L. et al. 8-Arylsulfanyl and 8-arylsulfoxyl adenine derivatives as inhibitors of the heat shock protein 90. J. Med. Chem. 48, 2892–2905 (2005).
He, H. et al. Identification of potent water-soluble purine-scaffold inhibitors of the heat shock protein 90. J. Med. Chem. 49, 381–390 (2006).
Chiosis, G., Caldas Lopes, E. & Solit, D. Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agents. Curr. Opin. Investig. Drugs 7, 534–541 (2006).
Viktorsson, K., Lewensohn, R. & Zhivotovsky, B. Apoptotic pathways and therapy resistance in human malignancies. Adv. Cancer Res. 94, 143–196 (2005).
Jiang, X. & Wang, X. Cytochrome C-mediated apoptosis. Annu. Rev. Biochem. 73, 87–106 (2004).
Gao, Z., Shao, Y. & Jiang, X. Essential roles of the Bcl-2 family of proteins in caspase-2-induced apoptosis. J. Biol. Chem. 280, 38271–38275 (2005).
Susin, S.A. et al. Mitochondrial release of caspase-2 and -9 during the apoptotic process. J. Exp. Med. 189, 381–394 (1999).
Fortugno, P. et al. Regulation of survivin function by Hsp90. Proc. Natl. Acad. Sci. USA 100, 13791–13796 (2003).
Downward, J. PI3-kinase, Akt and cell survival. Semin. Cell Dev. Biol. 15, 177–182 (2004).
Basso, A.D. et al. Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J. Biol. Chem. 277, 39858–39866 (2002).
Xu, W. et al. Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J. Biol. Chem. 276, 3702–3708 (2001).
El-Ashry, D., Miller, D.L., Kharbanda, S., Lippman, M.E. & Kern, F.G. Constitutive Raf-1 kinase activity in breast cancer cells induces both estrogen-independent growth and apoptosis. Oncogene 15, 423–435 (1997).
Ferguson, H.A., Marietta, P.M. & Van Den Berg, C.L. UV-induced apoptosis is mediated independent of caspase-9 in MCF-7 cells: a model for cytochrome c resistance. J. Biol. Chem. 278, 45793–45800 (2003).
Hostein, I. et al. Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis. Cancer Res. 61, 4003–4009 (2001).
Jäättelä, M. Escaping cell death: survival proteins in cancer. Exp. Cell Res. 248, 30–43 (1999).
Brodsky, J.L. & Chiosis, G. Hsp70 molecular chaperones: emerging roles in human disease and identification of small molecule modulators. Curr. Top. Med. Chem. 6, 1215–1225 (2006).
Fewell, S.W. et al. Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity. J. Biol. Chem. 279, 51131–51140 (2004).
Wei, Y.Q. et al. Induction of apoptosis by quercetin: involvement of heat shock protein. Cancer Res. 54, 4952–4957 (1994).
Koishi, M. et al. The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo. Clin. Cancer Res. 7, 215–219 (2001).
Nylandsted, J. et al. Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc. Natl. Acad. Sci. USA 97, 7871–7876 (2000).
Nylandsted, J. et al. Eradication of glioblastoma, and breast and colon carcinoma xenografts by Hsp70 depletion. Cancer Res. 62, 7139–7142 (2002).
Bagatell, R. et al. Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of hsp90-binding agents. Clin. Cancer Res. 6, 3312–3318 (2000).
Jackman, D.M. & Johnson, B.E. Small-cell lung cancer. Lancet 366, 1385–1396 (2005).
Sandler, A.B. Chemotherapy for small cell lung cancer. Semin. Oncol. 30, 9–25 (2003).
Mirski, S.E., Gerlach, J.H. & Cole, S.P. Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin. Cancer Res. 47, 2594–2598 (1987).
Warshamana-Greene, G.S. et al. The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin. Cancer Res. 11, 1563–1571 (2005).
Pandey, P. et al. Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J. 19, 4310–4322 (2000).
Saleh, A., Srinivasula, S.M., Balkir, L., Robbins, P.D. & Alnemri, E.S. Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat. Cell Biol. 2, 476–483 (2000).
Tian, Z.Q. et al. Synthesis and biological activities of novel 17-aminogeldanamycin derivatives. Bioorg. Med. Chem. 12, 5317–5329 (2004).
Moulick, K. et al. Synthesis of a red-shifted fluorescence polarization probe for Hsp90. Bioorg. Med. Chem. Lett. 16, 4515–4518 (2006).
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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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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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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DOI: https://doi.org/10.1038/nchembio.2007.10
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