title: GSK3β and Gli3 play a role in activation of Hedgehog-Gli pathway in human colon cancer - Targeting GSK3β downregulates the signaling pathway and reduces cell proliferation.
abstract: The role of Hedgehog-Gli (Hh-Gli) signaling in colon cancer tumorigenesis has not yet been completely elucidated. Here we provide strong evidence of Hh-Gli signaling involvement in survival of colon cancer cells, with the main trigger of activation being deregulated GSK3β. Our clinical data reveals high expression levels of GSK3β and Gli3 in human colon cancer tissue samples, with positive correlation between GSK3β expression and DUKES' stage. Further experiments on colon cancer cell lines have shown that a deregulated GSK3β upregulates Hh-Gli signaling and positively affects colon cancer cell survival. We show that inhibition of GSK3β with lithium chloride enhances Gli3 processing into its repressor form, consequently downregulating Hh-Gli signaling, reducing cell proliferation and inducing cell death. Analysis of the molecular mechanisms revealed that lithium chloride enhances Gli3-SuFu-GSK3β complex formation leading to more efficient Gli3 cleavage and Hh-Gli signaling downregulation. This work proposes that activation of the Hh-Gli signaling pathway in colon cancer cells occurs non-canonically via deregulated GSK3β. Gli3 seems to be the main pathway effector, highlighting the activator potential of this transcription factor, which is highly dependent on GSK3β function and fine tuning of the Gli3-SuFu-GSK3β platform.
authors.affiliation: Department of Molecular Medicine, Rudjer Boskovic Institute, Bijenička 54, Zagreb, Croatia. Electronic address: diana.trnski@irb.hr.
authors.forename: Diana
authors.initials: D
authors.lastname: Trnski
authors.affiliation: Department of Molecular Medicine, Rudjer Boskovic Institute, Bijenička 54, Zagreb, Croatia. Electronic address: maja.sabol@irb.hr.
authors.forename: Maja
authors.initials: M
authors.lastname: Sabol
authors.affiliation: Department of Surgery, University Hospital Center Zagreb, Kišpatićeva 12, Zagreb, Croatia. Electronic address: ante.gojevic@xnet.hr.
authors.forename: Ante
authors.initials: A
authors.lastname: Gojević
authors.affiliation: Department of Molecular Medicine, Rudjer Boskovic Institute, Bijenička 54, Zagreb, Croatia. Electronic address: marina.martinic.87@gmail.com.
authors.forename: Marina
authors.initials: M
authors.lastname: Martinić
authors.affiliation: Department of Molecular Medicine, Rudjer Boskovic Institute, Bijenička 54, Zagreb, Croatia. Electronic address: pozretic@irb.hr.
authors.forename: Petar
authors.initials: P
authors.lastname: Ozretić
authors.affiliation: Department of Molecular Medicine, Rudjer Boskovic Institute, Bijenička 54, Zagreb, Croatia. Electronic address: vmusani@irb.hr.
authors.forename: Vesna
authors.initials: V
authors.lastname: Musani
authors.affiliation: Department of Pathology, University Hospital for Tumors, Sestre milosrdnice University Hospital Center, Ilica 197, Zagreb, Croatia. Electronic address: snjezana.ramic@zg.t-com.hr.
authors.forename: Snježana
authors.initials: S
authors.lastname: Ramić
authors.affiliation: Department of Molecular Medicine, Rudjer Boskovic Institute, Bijenička 54, Zagreb, Croatia. Electronic address: levanat@irb.hr.
authors.forename: Sonja
authors.initials: S
authors.lastname: Levanat
keywords: Apoptosis; Autophagy; Colon cancer; GSK3β; Gli3; Hedgehog signaling