title: Synergistic inhibition of colon carcinoma cell growth by Hedgehog-Gli1 inhibitor arsenic trioxide and phosphoinositide 3-kinase inhibitor LY294002.
abstract: 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.
authors.affiliation: Colorectal Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Cai
authors.affiliation: Colorectal Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Pathology, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Colorectal Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Colorectal Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Colorectal Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Colorectal Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Lincan
authors.initials: L
authors.lastname: Duan
authors.affiliation: Colorectal Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Colorectal Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
authors.forename: Weiya
authors.initials: W
authors.lastname: Wang
keywords: Gli; Hedgehog pathway; LY294002; PI3K; arsenic trioxide; colon carcinoma cell