Scientific Publications by FDA Staff

Clin Cancer Res 2008 Jan 15;14(2):559-68

Effects of Plasmid-Based Stat3-Specific Short Hairpin RNA and GRIM-19 on PC-3M Tumor Cell Growth.

Zhang L, Gao L, Li Y, Lin G, Shao Y, Ji K, Yu H, Hu J, Kalvakolanu DV, Kopecko DJ, Zhao X, Xu DQ

Zhao, XJ (reprint author), Jilin Univ, Sch Basic Med, Prostate Dis Prevent & Treatment Res Ctr, Xinminn St, Changchun 130021, Peoples R China Jilin Univ, Sch Basic Med, Prostate Dis Prevent & Treatment Res Ctr, Changchun 130021, Peoples R China Jilin Univ, Sch Basic Med, Dept Pathophysiol, Changchun 130021, Peoples R China Univ Maryland, Greenebaum Canc Ctr, Dept Microbiol & Immunol, Program Mol Biol, Baltimore, MD 21201 USA US FDA, Ctr Biol Evaluat & Res, Lab Enter & Sexually Transmitted Dis, Bethesda, MD USA

PURPOSE: Persistent activation of signal transducers and activators of transcription 3 (Stat3) and its overexpression contribute to the progression and metastasis of several different tumor types. For this reason, Stat3 is a reasonable target for RNA interference-mediated growth inhibition. Blockade of Stat3 using specific short hairpin RNAs (shRNA) can significantly reduce prostate tumor growth in mice. However, RNA interference does not fully ablate target gene expression in vivo, owing to the idiosyncrasies associated with shRNAs and their targets. To enhance the therapeutic efficacy of Stat3-specific shRNA, we applied a combination treatment involving gene associated with retinoid-IFN-induced mortality 19 (GRIM-19), another inhibitor of STAT3, along with shRNA. EXPERIMENTAL DESIGN: The coding sequences for GRIM-19, a cellular STAT3-specific inhibitor, and Stat3-specific shRNAs were used to create a dual expression plasmid vector and used for prostate cancer therapy in vitro and in mouse xenograft models in vivo. RESULTS: The coexpressed Stat3-specific shRNA and GRIM-19 synergistically and more effectively suppressed prostate tumor growth and metastases when compared with treatment with either single agent alone. CONCLUSION: The simultaneous use of two specific, but mechanistically different, inhibitors of STAT3 activity exerts enhanced antitumor effects.