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

Trnski, Diana; Sabol, Maja; Gojević, Ante; Martinić, Marina; Ozretić, Petar; Musani, Vesna; Ramić, Snježana; Levanat, Sonja (2015) 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. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1852 (12). pp. 2574-2584. ISSN 0925-4439

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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.

Item Type:	Article
Uncontrolled Keywords:	Hedgehog signaling; Gli3; GSK3β; autophagy; apoptosis; colon cancer
Subjects:	BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
Divisions:	Division of Molecular Medicine
Projects:	Project title Project leader Project code Project type Signal transduction in tumors: Hh-Gli interactions and therapeutic potential (Prijenos signala u tumorima: Hh-Gli put, interakcije i potencijalne terapije)- Sonja Levanat 098-0982464-2461 MZOS
Depositing User:	Maja Sabol
Date Deposited:	27 Nov 2015 13:27
URI:	http://fulir.irb.hr/id/eprint/2305
DOI:	10.1016/j.bbadis.2015.09.005

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