Abstract
Based on recent reports that peroxisome proliferator-activated receptor delta (PPARδ) activation promotes tumourigenesis, we have investigated the role of this protein in Apc-mediated intestinal tumourigenesis. We demonstrate that the inactivation of Apc in the adult small intestine, while causing the expected nuclear accumulation of β-catenin, does not cause the expected increase in PPARδ mRNA or protein but conversely, the levels of PPARδ mRNA and protein are lowered. Furthermore, we find that ApcMinPPARδ-null mice exhibit an increased predisposition to intestinal tumourigenesis. Our data suggest that PPARδ is not directly regulated by β-catenin, and that inhibition of PPARδ activity is unlikely to be an appropriate strategy for the chemoprevention or chemotherapy of intestinal malignancies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM, Boland R and Evans RM . (2002). Proc. Natl. Acad. Sci. USA, 99, 303–308.
Chen L-C, Hao C-Y, Chiu YSY, Wong P, Melnick JS, Brotman M, Moretto J, Mendes F, Smith AP, Bennington JL, Moore D and Lee NM . (2004). Cancer Res., 64, 3694–3700.
Gupta RA, Tan J, Krause WF, Geraci MW, Willson TM, Dey SK and DuBois RN . (2000). Proc. Natl. Acad. Sci. USA, 97, 13275–13280.
Gupta RA, Wang D, Katkuri S, Wang H, Dey SK and DuBois RN . (2004). Nat. Med., 10, 245–247.
Harman FS, Nicol CJ, Marin HE, Ward JM, Gonzalez FJ and M Peters JM . (2004). Nat. Med., 10, 481–483.
He TC, Chan TA, Vogelstein B and Kinzler KW . (1999). Cell, 99, 335–345.
Ireland H, Kemp R, Houghton C, Howard L, Clarke AR, Sansom OJ and Winton DJ . (2004). Gastroenterology, 126, 1236–1246.
Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P and McKechnie D . (1991). Science, 253, 661–665.
Kongkanuntn R, Bubb VJ, Sansom OJ, Wyllie AH, Harrison DJ and Clarke AR . (1999). Oncogene, 18, 7219–7225.
Notterman DA, Alon U, Sierk AJ and Levine AJ . (2001). Cancer Res., 61, 3124–3130.
Orner GA, Dashwood W-M, Blum CA, Diaz GD and Dashwood RH . (2003). Carcinogenesis, 24, 263–267.
Park BH, Vogelstein B and Kinzler KW . (2001). Proc. Natl. Acad. Sci. USA, 98, 2598–2603.
Peters JM, Lee SS, Li W, Ward JM, Gavrilova O, Everett C, Reitman ML, Hudson LD and Gonzalez FJ . (2000). Mol. Cell. Biol., 20, 5119–5128.
Rosenberger TA, Hovda JT and Peters JM . (2002). Lipids, 37, 495–500.
Sansom OJ, Berger J, Bishop SM, Hendrich B, Bird A and Clarke AR . (2003). Nat. Genet., 34, 145–147.
Sansom OJ, Reed KR, Hayes AJ, Ireland H, Brinkmann H, Newton IP, Batlle E, Simon-Assmann P, Clevers H, Nathke IS, Clarke AR and Winton DJ . (2004). Gen. Dev., 18, 1385–1390.
Shibata H, Toyama K, Shioya H, Ito M, Hirota M, Hasegawa S, Matsumoto H, Takano H, Akiyama T, Toyoshima K, Kanamaru R, Kanegae Y, Saito I, Nakamura Y, Shiba K and Noda T . (1997). Science, 278, 120–123.
Shureiqi I, Jiang W, Zuo X, Wu Y, Stimmel JB, Leesnitzer LM, Morris JS, Fan HZ, Fischer SM and Lippman SM . (2003). Proc. Natl. Acad. Sci USA, 100, 9968–9973.
Stephen RL, Gustafsson MC, Jarvis M, Tatoud R, Marshall BR, Knight D, Ehrenborg E, Harris AL, Wolf CR and Palmer CN . (2004). Cancer Res., 64, 3162–3170.
Van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R and Clevers H . (2002). Cell, 111, 241–250.
Acknowledgements
We thank Derek Scarborough and Mark Bishop for technical assistance, and also Inke Nathke and Ian Newton for assistance with Western analysis. This work was supported by a programme grant from Cancer Research UK, a grant from the CR-UK New Targets Initiative and the Wales Gene Park.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary information accompanies the paper on Oncogene website (http://www.nature.com/onc).
Supplementary information
Rights and permissions
About this article
Cite this article
Reed, K., Sansom, O., Hayes, A. et al. PPARδ status and Apc-mediated tumourigenesis in the mouse intestine. Oncogene 23, 8992–8996 (2004). https://doi.org/10.1038/sj.onc.1208143
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208143
Keywords
This article is cited by
-
Unraveling the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) expression in colon carcinogenesis
npj Precision Oncology (2019)
-
Genetic Variants of Peroxisome Proliferator-Activated Receptor δ Are Associated with Gastric Cancer
Digestive Diseases and Sciences (2013)
-
Transcription factor AP1 binds the functional region of the promoter and regulates gene expression of human PPARdelta in LoVo cell
Tumor Biology (2013)
-
The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention
Nature Reviews Cancer (2012)
-
Peroxisome proliferator activating receptor (PPAR) in cerebral malaria (CM): a novel target for an additional therapy
European Journal of Clinical Microbiology & Infectious Diseases (2011)