PPARs and their role in cancer Review article
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Published:
Dec 30, 2011
Keywords:
PPAR, nucelar receptors, clinical trials, neoplasms, cancerogenesis
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Abstract
Peroxisome proliferator activated receptors are members of a very common group of steroid nuclear receptors. The aim of the study was to present actual knowledge regarding the role of PPAR in cancerogenesis. Three types of PPAR are identified: PPARα, PPARβ/δ and PPARγ. They all belong to the superfamily of nuclear receptors and are similar to vitamine D receptor, thyroid hormone receptor and retinoid receptor. In physiological conditions PPAR participates in adipocyte differentiation, lipid storage, regulation of inflamatory reaction as well as in glucose metabolism. Since 1990s the role of PPAR in cancerogenesis has been emphasised. PPARα plays a significant role in cancerogenesis of hepatocellular cancer. Activation of PPARβ/δ is crucial in developing the colorectal cancer in patients with familial adenomatous polyposis. The role of PPARγ in cancerogenesis is more complex. PPARγ can inhibit proliferation of cancer cells and they have some antiangiogenic and proapoptic activity in tumor. So far the clinical use of PPAR ligands as anticancer agents is limited to phase I and II clinical trials, available results of which are unclear.
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Głogowski Łukasz, Żmuda-Siedlarczyk A, Witkoś A, Rusinowska Z, Kokot T, Muc-Wierzgoń M, Nowakowska-Zajdel E. PPARs and their role in cancer. OncoReview [Internet]. 2011Dec.30 [cited 2024Nov.23];1(4(4):279-84. Available from: https://journalsmededu.pl/index.php/OncoReview/article/view/285
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Copyright: © Medical Education sp. z o.o. This is an Open Access article distributed under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). License (https://creativecommons.org/licenses/by-nc/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
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References
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19. He T.C., Chan T.A., Vogelstein B., Kinzler K.W.: PPARδ is an APC-regulated target of nonsteroidal antiinflammatory drugs. Cell 1999; 99(3): 335-345.
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21. Patel L., Pass I., Coxon P., Downes C.P., Smith S.A., Macphee C.H.: Tumor suppressor and antiinflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr. Biol. 2001; 11: 764-768.
22. Kitamura S., Miyazaki Y., Hiraoka S. et al.: PPARγ agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells. International Journal of Cancer 2001; 94(3): 335-342.
23. Bonofiglio D., Gabriele S., Aquila S., Qi H., Belmonte M., Catalano S. et al.: Peroxisome proliferator-activated receptor gamma activates fas ligand gene promoter inducing apoptosis in human breast cancer cells. Breast Cancer Res. Treatment 2009; 113(3): 423-434.
24. Ohta K., Endo T., Haraguchi K., Hershman J.M., Onaya T.: Ligands for peroxisome proliferator-activated receptor gamma inhibit growth and induce apoptosis of human papillary thyroid carcinoma cells. The Journal of Clinical Endocrinology and Metabolism 2001; 86: 2170-2177.
25. Yang W.L., Frucht H.: Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells. Carcinogenesis 2001; 22(9): 1379-1383.
26. Barak Y., Nelson M.C., Ong E.S., Jones Y.Z., Ruiz-Lozano P., Chien K.R. et al.: PPARgamma is required for placental, cardiac and adipose tissue development. Molecular Cell 1999; 4: 585-595.
27. Panigrahy D., Singer S., Shen L.Q., Butterfield C.E., Freedman D.A., Chen E.J. et al.: PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. The Journal of Clinical Investigation 2002; 110: 923-932.
28. Xin X., Yang S., Kowalski J., Gerritsen M.E.: Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. The Journal of Biological Chemistry 1999; 274: 9116-9121.
29. Goetze S., Bungenstock A., Czupalla C., Eilers F., Stawowy P., Kintscher U. et al.: Leptin induces endothelial cell migration through Akt, which is inhibited by PPARgamma-ligands. Hypertension 2002; 40: 748-754.
30. Kulke M.H., Demetri G.D., Sharpless N.E., Ryan D.P., Shivdasani R., Clark J.S.: A phase II study of troglitazone, an activator of the PPARgamma receptor, in patients with chemotherapy-resistant metastatic colorectal cancer. Cancer J. 2002; 8(5): 395-399.
31. Online: www.clinicaltrials.gov.
32. Saif M.W., Oettle H., Vervenne W.L., Thomas J.P., Spitzer G., Visseren-Grul C., Enas N., Richards D.A.: Randomized double-blind phase II trial comparing gemcitabine plus LY293111 versus gemcitabine plus placebo in advanced adenocarcinoma of the pancreas. Cancer J. 2009; 15(4): 339-343.
33. Smith M.R., Manola J., Kaufman D.S., George D., Oh W.K., Mueller E., Spiegelman B., Small E., Kantoff P.W.: Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy. Cancer 2004; 101(7): 1569-1574.
34. Tenenbaum A., Boyko V., Fisman E.Z., Goldenberg I., Adler Y., Feinberg M.S., Motro M., Tanne D., Shemesh J., Schwammenthal E., Behar S.: Does the lipid-lowering peroxisome proliferator-activated receptors ligand bezafibrate prevent colon cancer in patients with coronary artery disease? Cardiovasc. Diabetol. 2008; 19(7): 18.
35. Ogino S., Shima K., Baba Y., Nosho K., Irahara N., Kure S., Chen L., Toyoda S., Kirkner G.J., Wang Y.L., Giovannucci E.L., Fuchs C.S.: Colorectal
cancer expression of peroxisome proliferator-activated receptor gamma (PPARgamma) is associated with good prognosis. Gastroenterology 2009; 136(4): 1242-1250.
2. Issemann I., Green S.: Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990; 347(6294): 645-650.
3. Desvergne B., Wahli W.: Peroxisome proliferators activated receptors: nuclear control of metabolism. Endocrinology Rev. 1999; 20(5): 649-688.
4. Mandard S., Müller M., Kersten S.: Peroxisome proliferator-activated receptor α target genes. Cellular and Molecular Life Sciences 2004; 60: 393-416.
5. Krey G., Braissant O., l’Horset F. et al.: Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivatordependent receptor ligand assay. Mol. Endocrinology 1997; 11: 779-791.
6. Forman B.M., Chen J., Evans R.M.: Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proceedings of the National Academy of Sciences of the United States of America 1997; 94(9): 4312-4317.
7. Kliewer S.A., Sundseth S.S., Jones S.A. et al.: Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proceedings of the National Academy of Sciences of the United States of America 1997; 94(9): 4318-4323.
8. Lock E.A., Mitchell A.M., Elcombe C.R.: Biochemical mechanisms of induction of hepatic peroxisome proliferation. Annual Review of Pharmacology and Toxicology 1989; 29: 145-163.
9. Auboeuf D., Rieusset J., Fajas L. et al.: Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver x receptoralpha in humans: no alteration in adipose tissue of obese and niddm patients. Diabetes 1997; 46(8): 1319-1327.
10. Fajas L., Auboeuf D., Raspe E. et al.: The organization, promoter analysis, and expression of the human ppargamma gene. The Journal of Biological Chemistry 1997; 272(30): 18779-18789.
11. Ashby J., Brady A., Elcombe C.R. et al.: Mechanistically based human hazard assessment of peroxisome proliferatorinduced hepatocarcinogenesis. Human & Experimental Toxicology 1994; 13(suplement 2): S1-S117.
12. Patofizjologia i następstwa kliniczne insulinooporności. Kinalska I. (red.). WIG-Press, 2004: 267-272.
13. McKenna N.J., O’Malley B.W.: Minireview: nuclear receptor coactivators – an update. Endocrinology 2002; 143: 2461-2465.
14. Ricote M., Glass C.K.: PPARs and molecular mechanisms of transrepression. Biochimica et Biophysica Acta 2007; 1771: 926-35.
15. Peters J.M., Cattley R.C., Gonzalez F.J.: Role of PPARα in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis 1997; 18(11): 2029-2033.
16. Goel S.K., Lalwani N.D., Reddy J.K.: Peroxisome proliferation and lipid peroxidation in rat liver. Cancer Research 1986; 46(3): 1324-1330.
17. Bieri F., Bentley P., Waechter F., Staubli W.: Use of primary cultures of adult rat hepatocytes to investigatemechanisms of action of nafenopin, a hepatocarcinogenic peroxisome proliferator. Carcinogenesis 1984; 5(8): 1033-1039.
18. Gupta R.A., Tan J., Krause W.F. et al.: Prostacyclin-mediated activation of peroxisome proliferator-activated receptor δ in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America 2000; 97(24): 13275-13280.
19. He T.C., Chan T.A., Vogelstein B., Kinzler K.W.: PPARδ is an APC-regulated target of nonsteroidal antiinflammatory drugs. Cell 1999; 99(3): 335-345.
20. Shimada T., Kojima K., Yoshiura K., Hiraishi H., Terano A.: Characteristics of the peroxisome proliferator activated receptor γ (PPARγ) ligand induced apoptosis in colon cancer cells. Gut 2002; 50(5): 658-664.
21. Patel L., Pass I., Coxon P., Downes C.P., Smith S.A., Macphee C.H.: Tumor suppressor and antiinflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr. Biol. 2001; 11: 764-768.
22. Kitamura S., Miyazaki Y., Hiraoka S. et al.: PPARγ agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells. International Journal of Cancer 2001; 94(3): 335-342.
23. Bonofiglio D., Gabriele S., Aquila S., Qi H., Belmonte M., Catalano S. et al.: Peroxisome proliferator-activated receptor gamma activates fas ligand gene promoter inducing apoptosis in human breast cancer cells. Breast Cancer Res. Treatment 2009; 113(3): 423-434.
24. Ohta K., Endo T., Haraguchi K., Hershman J.M., Onaya T.: Ligands for peroxisome proliferator-activated receptor gamma inhibit growth and induce apoptosis of human papillary thyroid carcinoma cells. The Journal of Clinical Endocrinology and Metabolism 2001; 86: 2170-2177.
25. Yang W.L., Frucht H.: Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells. Carcinogenesis 2001; 22(9): 1379-1383.
26. Barak Y., Nelson M.C., Ong E.S., Jones Y.Z., Ruiz-Lozano P., Chien K.R. et al.: PPARgamma is required for placental, cardiac and adipose tissue development. Molecular Cell 1999; 4: 585-595.
27. Panigrahy D., Singer S., Shen L.Q., Butterfield C.E., Freedman D.A., Chen E.J. et al.: PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. The Journal of Clinical Investigation 2002; 110: 923-932.
28. Xin X., Yang S., Kowalski J., Gerritsen M.E.: Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. The Journal of Biological Chemistry 1999; 274: 9116-9121.
29. Goetze S., Bungenstock A., Czupalla C., Eilers F., Stawowy P., Kintscher U. et al.: Leptin induces endothelial cell migration through Akt, which is inhibited by PPARgamma-ligands. Hypertension 2002; 40: 748-754.
30. Kulke M.H., Demetri G.D., Sharpless N.E., Ryan D.P., Shivdasani R., Clark J.S.: A phase II study of troglitazone, an activator of the PPARgamma receptor, in patients with chemotherapy-resistant metastatic colorectal cancer. Cancer J. 2002; 8(5): 395-399.
31. Online: www.clinicaltrials.gov.
32. Saif M.W., Oettle H., Vervenne W.L., Thomas J.P., Spitzer G., Visseren-Grul C., Enas N., Richards D.A.: Randomized double-blind phase II trial comparing gemcitabine plus LY293111 versus gemcitabine plus placebo in advanced adenocarcinoma of the pancreas. Cancer J. 2009; 15(4): 339-343.
33. Smith M.R., Manola J., Kaufman D.S., George D., Oh W.K., Mueller E., Spiegelman B., Small E., Kantoff P.W.: Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy. Cancer 2004; 101(7): 1569-1574.
34. Tenenbaum A., Boyko V., Fisman E.Z., Goldenberg I., Adler Y., Feinberg M.S., Motro M., Tanne D., Shemesh J., Schwammenthal E., Behar S.: Does the lipid-lowering peroxisome proliferator-activated receptors ligand bezafibrate prevent colon cancer in patients with coronary artery disease? Cardiovasc. Diabetol. 2008; 19(7): 18.
35. Ogino S., Shima K., Baba Y., Nosho K., Irahara N., Kure S., Chen L., Toyoda S., Kirkner G.J., Wang Y.L., Giovannucci E.L., Fuchs C.S.: Colorectal
cancer expression of peroxisome proliferator-activated receptor gamma (PPARgamma) is associated with good prognosis. Gastroenterology 2009; 136(4): 1242-1250.