Aberrant activation of
Signal Transducer and Activator of Transcription 3 (STAT3) signaling has been shown to be associated with uncontrolled cell proliferation and suppression of host-immune surveillance. Conversely, silencing STAT3 can have the dual effects of inhibiting
cancer cell proliferation and inducing anti-
tumor immune responses. Here, we report on the effects of STAT3 silencing on suicide gene therapy with
thymidine kinase (tk). STAT3 silencing by
siRNA inhibited the proliferation of AGS human
gastric cancer cells through G1 cell cycle arrest, decreased levels of immune-suppressive
cytokines, and increased levels of immune-activating
cytokines. CT26 mouse
colon adenocarcinoma cells, in which STAT3 expression was knocked-down by a STAT3
shRNA-containing lentivirus, grew more slowly in syngenic model Balb/c mice than control CT26 cells. Moreover, we found that STAT3 silencing augmented the efficacy of suicide gene therapy in CT26 cell xenografted mice. When we administrated adenoviruses harboring the herpes simplex virus
thymidine kinase gene (Ad5.CMV.HSV.tk) into STAT3-silenced CT26 cell
tumors, extensive apoptosis was observed and there was a significant reduction in the size of CT26 cell
tumors. STAT3 silencing also enhanced the recruitment and cytotoxic activity of CD3(+)CD8(+) T-cells, and changed the
cytokine expression pattern of CT26 cell
tumors, reflecting augmentation of anti-
cancer immune responses. We conclude that combining suicide gene therapy with STAT3 silencing can result in enhanced anti-
cancer effects.