Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1

Cancer Gene Ther. 2008 Jan;15(1):29-39. doi: 10.1038/sj.cgt.7701094. Epub 2007 Sep 7.


FUS1 is a novel tumor suppressor gene located in the human chromosome 3p21.3 region. We previously showed that restoration of FUS1 function in 3p21.3-deficient human non-small-cell lung cancer (NSCLC) cells significantly inhibited tumor cell growth in vitro and in vivo. In this study, we evaluated the combined effects of the tumor suppressor FUS1 and the chemotherapeutic drug cisplatin on tumor cell growth and apoptosis induction in NSCLC cells, and explored the molecular mechanism of their mutual action. Exogenous expression of FUS1 by nanoparticle-mediated gene transfer sensitized the response of NSCLC cells to cisplatin, resulting in a 4- to 6-fold increase in tumor-suppressing activity. A systemic treatment with a combination of FUS1-nanoparticles and cisplatin in a human H322 lung cancer orthotopic xenograft mouse model dramatically enhanced the therapeutic efficacy of cisplatin. We also found that the FUS1-enhanced chemosensitivity is associated with the downregulation of MDM2, accumulation of p53 and activation of the Apaf-1-dependent apoptosis pathway. Our results demonstrated an important role of FUS1 in modulating chemosensitivity of lung cancer cells, and suggested that a proper combination of molecular therapeutics such as the proapoptotic tumor suppressor FUS1 and the conventional chemotherapeutic drugs such as cisplatin may be an efficient treatment strategy for human lung cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptotic Protease-Activating Factor 1 / biosynthesis
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 3 / genetics
  • Chromosomes, Human, Pair 3 / metabolism
  • Cisplatin / pharmacology*
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / therapy*
  • Mice
  • Nanoparticles
  • Proto-Oncogene Proteins c-mdm2 / biosynthesis
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Proteins / biosynthesis*
  • Tumor Suppressor Proteins / genetics
  • Xenograft Model Antitumor Assays


  • APAF1 protein, human
  • Antineoplastic Agents
  • Apoptotic Protease-Activating Factor 1
  • TUSC2 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Cisplatin