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Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue

Cancer Gene Therapy volume 14, pages 12–18 (2007)Cite this article

Abstract

Our previous studies demonstrated that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7 (Ad-mda7) leads to rapid induction of double-stranded RNA-dependent protein kinase (PKR) and activation of its downstream targets, resulting in apoptosis induction in human lung cancer cells. Here, we report that Ad-mda7 and the benzoquinone ansamycin geldanamycin (GA) interact in a highly synergistic manner to induce cell death in human lung cancer cells. Co-administration of Ad-mda7 and GA did not modify expression of MDA-7, and was not associated with further PKR induction and activation; instead the enhanced cytotoxicity of this combination was associated with inactivation of AKT by GA. By surface staining using anti-E-cadherin monoclonal antibody and flow cytometry, we found that treatment with the combination of Ad-mda7 and GA increased E-cadherin levels in these cancer cells. Ad-mda7 and GA cotreatment also inhibited lung cancer cell motility by increasing the β-catenin/E-cadherin association. Moreover, combination of GA derivative 17-allyl-amino, 17-demethoxygeldanamycin (17AAG), with Ad-mda7 resulted in enhancement of cell death in A549 and H460 human lung cancer cells.

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References

  1. Jiang H, Lin JJ, Su ZZ, Goldstien NI, Fisher PB . Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995; 11: 2477–2486.

    CAS  Google Scholar 

  2. Sarkar D, Su ZZ, Lebedeva IV, Savane M, Gopalkrishman RV, Dent P et al. mda-7 (IL-24): Signaling and functional roles. Biotechniques Suppl 2002; 10: 30–39.

    Article  Google Scholar 

  3. Mhashilkar AM, Stewart AL, Sieger K, Yang HY, Khimani AH, Ho I et al. MDA-7 negatively regulates the beta-catenin and PI3K signaling pathways in breast and lung tumor cells. Mol Ther 2003; 8: 207–219.

    Article  CAS  Google Scholar 

  4. Mhashilkar AM, Schrock RD, Hindi M, Liao J, Sieger K, Kourouma F et al. Melanoma differentiation associated gene (mda7): a novel anti-tumor gene for cancer gene therapy. Mol Med 2001; 7: 271–282.

    Article  CAS  Google Scholar 

  5. Chada S, Mhashilkar AM, Ramesh R, Mumm JB, Sutton RB, Bocangel D et al. Bystander activity of Ad-mda7: MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism. Mol Ther 2004; 10: 1085–1095.

    Article  CAS  Google Scholar 

  6. Pataer A, Vorburger ST, Barber GN, Xia W, Chiao P, Ellis LM et al. Adenoviral transfer of the melanoma differentiation-associated gene 7 (mda7) induces apoptosis of lung cancer cells via up-regulation of the double-stranded RNA dependent protein kinase (PKR). Cancer Res 2002; 62: 2239–2243.

    CAS  Google Scholar 

  7. Williams B . Signal integration via PKR. Sci STKE 2001; 89: RE2.

    Google Scholar 

  8. Barber GN . Host defense, viruses and apoptosis. Cell Death Diff 2001; 8: 113–126.

    Article  CAS  Google Scholar 

  9. Jagus R, Joshi B, Barber GN . PKR, apoptosis and cancer. Int J Biochem Cell Biol 1999; 31: 123–138.

    Article  CAS  Google Scholar 

  10. Donze O, Abbas-Terki T, Picard D . The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR. EMBO J 2001; 20: 3771–3780.

    Article  CAS  Google Scholar 

  11. Solit DB, Scher HI, Rosen N . Hsp90 as a therapeutic target in prostate cancer. Semin Oncol 2003; 30: 709–716.

    Article  CAS  Google Scholar 

  12. Vorburger SA, Pataer A, Yoshida K, Barber GN, Xia W, Chiao P et al. Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis. Oncogene 2002; 21: 6278–6288.

    Article  CAS  Google Scholar 

  13. Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A et al. Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription. Cancer Res 2001; 61: 1671–1677.

    CAS  PubMed  Google Scholar 

  14. Sieger KA, Mhashilkar AM, Stewart A, Sutton RB, Strube RW, Chen SY et al. The tumor suppressor activity of MDA-7/IL-24 is mediated by intracellular protein expression in NSCLC cells. Mol Ther 2004; 9: 355–367.

    Article  CAS  Google Scholar 

  15. Ramesh R, Mhashilkar AM, Tanaka F, Saito Y, Branch DC, Sieger K et al. Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor. Cancer Res 2004; 63: 5105–5113.

    Google Scholar 

  16. Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM . Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 1999; 285: 107–110.

    Article  CAS  Google Scholar 

  17. Maloney A, Workman P . HSP90 as a new therapeutic target for cancer therapy: The story unfolds. Expert Opin Biol Ther 2002; 2: 3–24.

    Article  CAS  Google Scholar 

  18. Sausville EA, Tomaszewski JE, Ivy P . Clinical development of 17-allylamino, 17-demethoxygeldanamycin. Curr Cancer Drug Targets 2003; 3: 377–383.

    Article  CAS  Google Scholar 

  19. Downward J . PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 2004; 15: 177–182.

    Article  CAS  Google Scholar 

  20. Luo J, Manning BD, Cantley LC . Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 2003; 4: 257–262.

    Article  CAS  Google Scholar 

  21. Pandey P, Saleh A, Nakazawa A, Kumar S, Srinivasula SM, Kumar V et al. Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J 2000; 19: 4310–4322.

    Article  CAS  Google Scholar 

  22. Moon RT, Kohn AD, De Ferrari GV, Kaukas A . WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 2004; 5: 691–701.

    Article  CAS  Google Scholar 

  23. Pece S, Chiariello M, Murga C, Gutkind JS . Activation of the protein kinase Akt/PKB by the formation of E-cadherin-mediated cell-cell junctions. Evidence for the association of phosphatidylinositol 3-kinase with the E-cadherin adhesion complex. J Biol Chem 1999; 274: 19347–19351.

    Article  CAS  Google Scholar 

  24. Kobielak A, Fuchs E . Alpha-catenin: at the junction of intercellular adhesion and actin dynamics. Nat Rev Mol Cell Biol 2004; 5: 614–625.

    Article  CAS  Google Scholar 

  25. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 2003; 425: 407–410.

    Article  CAS  Google Scholar 

  26. Enmon R, Yang WH, Ballangrud AM, Solit DB, Heller G, Rosen N et al. Combination treatment with 17-N-allylamino-17-demethoxy geldanamycin and acute irradiation produces supra-additive growth suppression in human prostate carcinoma spheroids. Cancer Res 2003; 63: 8393–8399.

    CAS  PubMed  Google Scholar 

  27. Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N . Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res 2003; 63: 2139–2144.

    CAS  PubMed  Google Scholar 

  28. Rahmani M, Yu C, Dai Y, Reese E, Admed W, Dent P et al. Coadministration of the heat shock protein 90 antagonist 17-allylamino- 17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. Cancer Res 2003; 63: 8420–8427.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Cancer Institute and the National Institutes of Health (P01 CA78778-01A1) (JAR, SGS) SPORE 2P50-CA70970-04 and by SBIR 1R43 CA86587-1 (SGS, SC); by gifts to the Division of Surgery from Tenneco and Exxon for the Core Laboratory Facility; by the MD Anderson Cancer Center Support Core Grant (CA 16672); by donations from the Charles Rogers Memorial and Gene Therapy Donor funds; by a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature (Project 8); by the WM Keck Foundation; and by a sponsored research agreement with Introgen Therapeutics Inc. (SR93-004-1). We thank Alma Vega and Debbie Smith for their assistance in preparation of the manuscript.

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, Houston, TX, USA

    A Pataer, D Bocangel, J A Roth & S G Swisher

  2. Department of Introgen Therapeutics Inc., Houston, TX, USA

    S Chada

  3. Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K K Hunt

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  1. A Pataer
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Correspondence to A Pataer.

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Pataer, A., Bocangel, D., Chada, S. et al. Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue. Cancer Gene Ther 14, 12–18 (2007). https://doi.org/10.1038/sj.cgt.7700989

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