The Hedgehog (Hh) signaling pathway not only plays important roles in embryogenesis and adult tissue homeostasis, but also in
tumorigenesis. Aberrant Hh pathway activation has been reported in a variety of malignant
tumors including colon
carcinoma. Here, we sought to investigate the regulation of the Hh pathway
transcription factor Gli1 by
arsenic trioxide and
phosphoinositide 3-kinase (PI3K) inhibitor
LY294002 in colon
carcinoma cells. We transfected cells with siGli1 and observed a significant reduction of Gli1 expression in HCT116 and HT29 cells, which was confirmed by quantitative real-time polymerase chain reaction and Western blots. Knocking down endogenous Gli1 reduced colon
carcinoma cell viability through inducing cell apoptosis. Similarly, knocking down Gli2 using
short interfering RNA impaired colon
carcinoma cell growth in vitro. To elucidate the regulation of Gli1 expression, we found that both Gli inhibitor
arsenic trioxide and PI3K inhibitor
LY294002 significantly reduced
Gli1 protein expression and colon
carcinoma cell proliferation.
Arsenic trioxide treatment also reduced Gli1 downstream target gene expression, such as Bcl2 and CCND1. More importantly, the inhibition of Hedgehog-Gli1 by
arsenic trioxide showed synergistic anticancer effect with the PI3K inhibitor
LY294002 in colon
carcinoma cells. Our findings suggest that the Hh pathway
transcription factor Gli1 is involved in the regulation of colon
carcinoma cell viability. Inhibition of Hedgehog-Gli1 expression by
arsenic trioxide and PI3K inhibitor synergistically reduces
colon cancer cell proliferation, indicating that they could be used as an effective anti-
colon cancer combination
therapy.