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Urocanic acid-modified chitosan-mediated PTEN delivery via aerosol suppressed lung tumorigenesis in K-rasLA1 mice

Abstract

The low efficiency of conventional therapies in achieving long-term survival of lung cancer patients calls for development of novel options. Revisiting of aerosol gene delivery may provide an alternative for safe and effective treatment for lung cancer. In this study, imidazole ring-containing urocanic acid-modified chitosan (UAC) designed in the previous study was used as a gene carrier. The potential effects of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) on Akt-related signals and cell cycle regulation were evaluated. Aerosols of UAC–PTEN were delivered into K-rasLA1 lung cancer model mice through the nose-only inhalation system twice a week for total 4 weeks. Delivered PTEN suppressed lung tumor development significantly through nuclear complex formation between PTEN and p53, suppressing Akt-related signals as well as cell cycle regulation. Together, our results suggest that aerosol delivery of UAC–PTEN may be compatible with noninvasive in vivo gene therapy.

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References

  1. Dailey LA, Kleemann E, Merdan T, Petersen H, Schmehl T, Gessler T et al. Modified polyethylenimines as non-viral gene delivery systems for aerosol therapy: effects of nebulization on cellular uptake and transfection efficiency. J Control Release 2004; 100: 425–436.

    Article  CAS  PubMed  Google Scholar 

  2. Ferrari S, Geddes DM, Alton EW . Barriers to and new approaches for gene therapy and gene delivery in cystic fibrosis. Adv Drug Deliv 2002; 54: 1373–1393.

    Article  CAS  Google Scholar 

  3. Merdan T, Kopecek J, Kissel T . Prospects for cationic polymers in gene and oligonucleotide therapy against cancer. Adv Drug Deliv 2002; 54: 715–758.

    Article  CAS  Google Scholar 

  4. Gautam A, Densmore CL, Golunski E, Xu B, Waldrep JC . Transgene expression in mouse airway epithelium by aerosol gene therapy with PEI-DNA complexes. Mol Ther 2001; 3: 551–556.

    Article  CAS  PubMed  Google Scholar 

  5. Goula D, Becker N, Lemkine GF, Normandie P, Rodrigues J, Mantero S et al. Rapid crossing of the pulmonary endothelial barrier by polyethylenimine/DNA complexes. Gene Therapy 2000; 7: 499–504.

    Article  CAS  PubMed  Google Scholar 

  6. Densmore CL . Advances in noninvasive pulmonary gene therapy. Curr Drug Deliv 2006; 3: 55–63.

    Article  CAS  PubMed  Google Scholar 

  7. Merlin JL, Dolivet G, Dubessy C, Festor E, Parache RM, Verneuil L et al. Improvement of non-viral p53 gene transfer in human carcinoma cells using glucosylated polyethylenimine derivatives. Cancer Gene Ther 2001; 8: 203–210.

    Article  CAS  PubMed  Google Scholar 

  8. Jin H, Kim TH, Hwang SK, Chang SH, Kim HW, Anderson HK et al. Aerosol delivery of urocanic acid-modified chitosan/programmed cell death 4 complex regulated apoptosis, cell cycle, and angiogenesis in lungs of K-ras null mice. Mol Cancer Ther 2006; 5: 1041–1049.

    Article  CAS  PubMed  Google Scholar 

  9. Kim TH, Ihm JE, Choi YJ, Nah JW, Cho CS . Efficient gene delivery by urocanic acid-modified chitosan. J Control Release 2003; 93: 389–402.

    Article  CAS  PubMed  Google Scholar 

  10. Pellegata NS, Antoniono RJ, Redpath JL, Stanbridge EJ . DNA damage and p53-mediated cell cycle arrest: a reevaluation. Proc Natl Acad Sci USA 1996; 93: 15209–15214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 2001; 410: 1111–1116.

    Article  CAS  PubMed  Google Scholar 

  12. Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 2002; 8: 1178–1184.

    CAS  PubMed  Google Scholar 

  13. Maehama T, Dixon JE . The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-triphosphate. J Biol Chem 1998; 273: 13375–13378.

    Article  CAS  PubMed  Google Scholar 

  14. Lawlor MA, Alessi DR . PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 2001; 114: 2903–2910.

    CAS  PubMed  Google Scholar 

  15. Myers MP, Pass I, Batty IH, Van Der Kaay J, Stolarov JP, Hemmings BA et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci USA 1998; 95: 13513–13518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brognard J, Clark AS, Ni Y, Dennis PA . Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001; 61: 3986–3997.

    CAS  PubMed  Google Scholar 

  17. Okudela K, Hayashi H, Ito T, Yazawa T, Suzuki T, Nakane Y et al. K-ras gene mutation enhances motility of immortalized airway cells and lung adenocarcinoma cells via Akt activation. Am J Pathol 2004; 164: 91–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tehrani AM, Hwang SK, Kim TH, Jin H, Nah WS, Kwon JT et al. Aerosol delivery of Akt controls protein translation in the lungs of dual luciferase reporter mice. Gene Therapy 2007; 14: 451–458.

    Article  CAS  PubMed  Google Scholar 

  19. Saito S, Yamaguchi H, Higashimoto Y, Chao C, Xu Y, Fornace AJ et al. Phosphorylation site interdependence of human p53 post-translational modifications in response to stress. J Biol Chem 2003; 278: 37536–37544.

    Article  CAS  PubMed  Google Scholar 

  20. Feng Z, Hu W, De Stanchina E, Teresky AK, Jin S, Lowe S et al. The regulation of AMPK β1, TSC2, and PTEN expression by p53: Stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-Akt-mTOR pathways. Cancer Res 2007; 67: 3043–3053.

    Article  CAS  PubMed  Google Scholar 

  21. Mayo LD, Donner DB . The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci 2002; 27: 462–467.

    Article  CAS  PubMed  Google Scholar 

  22. Park MR, Han KO, Han IK, Cho MH, Nah JW, Choi YJ et al. Degradable polyethylenimine-alt-poly(ethylene glycol) copolymers as novel gene carriers. J Control Release 2005; 105: 367–380.

    Article  CAS  PubMed  Google Scholar 

  23. Kim HW, Park IK, Cho CS, Lee KH, Beck GR, Colburn NH et al. Aerosol delivery of glucosylated polyethylenimine/phosphatase and tensin homologue deleted on chromosome 10 complex suppresses Akt downstream pathways in the lung of K-ras null mice. Cancer Res 2004; 64: 7971–7976.

    Article  CAS  PubMed  Google Scholar 

  24. Hlobilkova A, Knillova J, Svachova M, Skypalova P, Krystof V, Kolar Z . Tumor suppressor PTEN regulates cell cycle and protein kinase B/Akt pathway in breast cancer cells. Anticancer Res 2006; 26: 1015–1022.

    CAS  PubMed  Google Scholar 

  25. Tang JM, He QY, Guo RX, Chang XJ . Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer 2006; 51: 181–191.

    Article  PubMed  Google Scholar 

  26. Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 2003; 3: 117–130.

    Article  CAS  PubMed  Google Scholar 

  27. Asnaghi L, Bruno P, Priulla M, Nicolin A . mTOR: a protein kinase switching between life and death. Pharmacol Res 2004; 50: 545–549.

    Article  CAS  PubMed  Google Scholar 

  28. Bjornsti MA, Houghton PJ . The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4: 335–348.

    Article  CAS  PubMed  Google Scholar 

  29. Backman S, Stambolic V, Mak T . PTEN function in mammalian cell size regulation. Curr Opin Neurobiol 2002; 12: 516–522.

    Article  CAS  PubMed  Google Scholar 

  30. Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J . mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 2004; 24: 200–216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schmelzle T, Hall MN . TOR, a central controller of cell growth. Cell 2000; 103: 253–262.

    Article  CAS  PubMed  Google Scholar 

  32. Hleb M, Murphy S, Wagner EF, Hanna NN, Sharma N, Park J et al. Evidence for cyclin D3 as a novel target of rapamycin in human T lymphocytes. J Biol Chem 2004; 297: 31948–33155.

    Article  Google Scholar 

  33. Liu F, Wagner S, Campbell RB, Nickerson JA, Schiffer CA, Ross AH . PTEN enters the nucleus by diffusion. J Cell Biochem 2005; 96: 221–234.

    Article  CAS  PubMed  Google Scholar 

  34. Ginn-Pease ME, Eng C . Increased nuclear phosphatase and tensin homologue deleted on chromosome 10 is associated with G0-G1 in MCF-7 cells. Cancer Res 2003; 63: 282–286.

    CAS  PubMed  Google Scholar 

  35. Su JD, Mayo LD, Donner DB, Durden DL . PTEN and phosphatidylinositol 3′-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment. Cancer Res 2003; 63: 3585–3592.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was partially supported by the grants from the KOSEF (M10534040002-06N3404-00210) of the Ministry of Science and Technology in Korea. MHC, SHC, MW, MSN were supported by the Nano Systems Institute-National Core Research Center (NSI-NCRC) program of KOSEF. HJ, CXX, YSC, JYS, SJP, ESL, SKH, JTK and AMT are also grateful for the award of the BK21 fellowship. KHL was supported by 21C Frontier Functional Human Genome Project (FG03-0601-003-1-0-0) and National Nuclear R&D Program from Ministry of Science and Technology.

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Correspondence to C-S Cho or M-H Cho.

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Jin, H., Xu, CX., Kim, HW. et al. Urocanic acid-modified chitosan-mediated PTEN delivery via aerosol suppressed lung tumorigenesis in K-rasLA1 mice. Cancer Gene Ther 15, 275–283 (2008). https://doi.org/10.1038/sj.cgt.7701116

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