Constitutive activation of
signal transducer and activator of transcription 3 (STAT3) is common in many human and murine
cancer cells, and its activation leads to cellular transformation. STAT3 pathway inhibitors have been reported to suppress
cancer growth. To investigate the antitumor effects of inhibiting the STAT3-mediated signaling cascade in the cancer microenvironment, using a molecular-targeting approach, we focused on the gene associated with
retinoid-IFN-induced mortality 19 (GRIM-19). GRIM-19 has been reported to interact physically with STAT3 and inhibit STAT3-dependent signal transduction. We used the nona-
arginine (R9)-protein transduction domain (R9-PTD) as a
protein carrier to induce high levels of GRIM-19 expression in vitro and in vivo. We generated an R9-PTD-containing GRIM-19 fusion
protein (rR9-GRIM19) and successfully induced overexpression in the cytoplasm of
cancer cells. Analysis of the expression of downstream molecules of STAT3 confirmed that in vitro rR9-GRIM19 treatment of constitutively activated STAT3 (STAT3c)
cancer cells significantly reduced STAT3-dependent transcription. Moreover, intratumoral
injections of rR9-GRIM19 in STAT3c
cancer-bearing mice significantly suppressed
tumor growth. These results suggest that intratumoral
injections of rR9-GRIM19 have potential as a novel anticancer
therapy in STAT3c
cancer due to their ability to inhibit STAT3-mediated signal transduction without major systemic side effects.