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World J Gastroenterol. Jun 21, 2014; 20(23): 7137-7151
Published online Jun 21, 2014. doi: 10.3748/wjg.v20.i23.7137
Emerging role of the β-catenin-PPARγ axis in the pathogenesis of colorectal cancer
Lina Sabatino, Massimo Pancione, Carolina Votino, Tommaso Colangelo, Angelo Lupo, Ettore Novellino, Antonio Lavecchia, Vittorio Colantuoni
Lina Sabatino, Massimo Pancione, Carolina Votino, Tommaso Colangelo, Angelo Lupo, Vittorio Colantuoni, Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy
Ettore Novellino, Antonio Lavecchia, Department of Pharmacy, “Drug Discovery” Laboratory, University of Naples “Federico II“, 80131 Naples, Italy
Author contributions: Sabatino L and Pancione M contributed equally to this work; Sabatino L, Pancione M, Lupo A and Colantuoni V designed research; Sabatino L, Votino C and Colangelo T performed research; Novellino E and Lavecchia A contributed to the new compounds/analytic tools; Votino C and Lupo A performed the literature search; Sabatino L, Pancione M, Lupo A and Colantuoni V wrote the paper; and all authors approved the final version.
Supported by Ministero dell’Istruzione, Università e Ricerca, MIUR-PRIN 2010-2011, No. prot. 2010W7YRLZ_003
Correspondence to: Vittorio Colantuoni, Professor, Department of Sciences and Technologies, University of Sannio, Via Port’Arsa, 11, 82100 Benevento, Italy. colantuoni@unisannio.it
Telephone: +39-824-305102 Fax: +39-824-305147
Received: October 15, 2013
Revised: January 15, 2014
Accepted: April 30, 2014
Published online: June 21, 2014
Processing time: 249 Days and 11.7 Hours
Abstract

Multiple lines of evidence indicate that Wnt/β-catenin signaling plays a fundamental role in colorectal cancer (CRC) initiation and progression. Recent genome-wide data have confirmed that in CRC this pathway is one of the most frequently modified by genetic or epigenetic alterations affecting almost 90% of Wnt/β-catenin gene members. A major challenge is thus learning how the corrupted coordination of this pathway is tied to other signalings to enhance cell growth. Peroxisome proliferator activated receptor γ (PPARγ) is emerging as a growth-limiting and differentiation-promoting factor. In tumorigenesis it exerts a tumor suppressor role and is potentially linked with the Wnt/β-catenin pathway. Based on these results, the identification of new selective PPARγ modulators with inhibitory effects on the Wnt/β-catenin pathway is becoming an interesting perspective. Should, in fact, these molecules display such properties, new research avenues would be opened aimed at developing new molecular targeted drugs. Herein, we review the basic principles and present new hypotheses underlying the crosstalk between Wnt/β-catenin and PPARγ signaling. Furthermore, we discuss the advances in our understanding as to how their altered regulation can culminate in colon cancer and the efforts aimed at designing novel PPARγ agonists endowed with Wnt/β-catenin inhibitory effects to be used as therapeutic and/or preventive agents.

Keywords: Colorectal cancer; Wnt/β-catenin pathway; Peroxisome proliferator-activated receptor γ; Genomic instability; Peroxisome proliferator activated receptor γ ligands

Core tip: Genetic and epigenetic modifications of the Wnt/β-catenin pathway play a fundamental role in the initiation and progression of colorectal cancer (CRC). The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) acts as a differentiation-promoting transcription factor with a potential link with Wnt/β-catenin. In this review, we discuss the basic principles underlying the crosstalk between Wnt/β-catenin and PPARγ signaling, present the most recent progress in understanding as to how their alterations can culminate in CRC and, finally, suggest new hypotheses and perspectives on the identification of selective PPARγ modulators endowed with Wnt/β-catenin inhibitory effects to be used as molecular targeted drugs.