Abstract
All-trans retinoic acid (ATRA) exerts tumor-inhibitory effects on acute leukemia and certain types of solid tumors. This study was designed to evaluate the mechanism on ATRA-mediated suppression of colon cancer based on the sonic hedgehog (Shh) signaling pathway.
Methods:
Normal intestinal epithelial cells and three colon cancer cell lines were studied to evaluate the inhibitory effect of ATRA on tumor cell activity. The inhibitory effect of ATRA on colon cancer was evaluated by cell invasion, migration, and apoptosis of HCT116 cells. Retinoic acid receptor (RAR)- and Shh-related protein expression was assessed.
Results:
ATRA administration inhibited the activity of three different colon cancer lines, but did not inhibit the activity of normal intestinal epithelial cells. Administration of ATRA induced apoptosis and restricted invasion and migration of HCT116 colon cancer cells. Administration of ATRA also increased expression of RAR and transmembrane receptor patched 1 (Ptch1), and decreased expression of the smoothened (Smo) and glioma-associated oncogene homolog1 (Gli-1). RARα and RARβ agonists inhibited Shh signaling, and the mediating effect of ATRA on Shh signaling was abolished by RARα or RARβ antagonists. The combination of purmorphamine (Smo agonist) and ATRA partially abolished the inhibitory effect of ATRA on the proliferation of colon cancer cells. In vivo studies showed that ATRA inhibited tumor growth, which was accompanied by down-regulation of the Shh signaling pathway.
Conclusions:
ATRA inhibits the growth of colon cancer by downregulating the Shh pathway, which further verifies the anticancer activity of ATRA.
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