Role of Peroxisome Proliferator Activated Receptor α in Pathogenesis of Colorectal Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WEI Renjie ¹ , YANG Lie ¹ , ZHANG Lie ¹ , LU You ² , HU Jiankun ¹ , MO Xianming ³ ,  ZHOU Zongguang. ¹

1.Department of Gastrointestinal Surgery， West China Hospital， Sichuan University， Chengdu 610041， Sichuan Province， China;;
2.Department of Oncology，West China Hospital， Sichuan University， Chengdu 610041， Sichuan Province， China;;
3.Laboratory of Stem Cell Biology，State Key Laboratory of Biotherapy， West China Hospital， Sichuan University， Chengdu 610041， Sichuan Province， China;

Corresponding author：

ZHOU Zongguang., Email: zhou767@163.com

Keywords：

Peroxisome proliferator activated receptor α; Colorectal cancer; Pathogenesis

Video：

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Objective 　To investigate the role of peroxisome proliferator activated receptor α （PPARα） in the pathogenesis of colorectal cancer.
Method 　The literatures about PPARα and the pathogenesis of colorectal cancer were reviewed and analyzed.
Result 　The relationships of PPARα to the proliferation， apoptosis， and differentiation of colorectal cancer cells in the pathogenesis of colorectal cancer were controversial.
Conclusions 　PPARα might be involved in the regulation of proliferation， differentiation， apoptosis of colorectal cancer cells， but the pathogenesis and the up- and down-stream signal pathways are not elucidated. In additional， PPARα might partly be involved in the mechanism of drug resistance of chemotherapy drugs for colorectal cancer， but the role is not very clear yet. So more research works need to be done about the relationship of PPARα to pathogenesis of colorectal cancer.

Citation： WEI Renjie,YANG Lie,ZHANG Lie,LU You,HU Jiankun,MO Xianming,ZHOU Zongguang.. Role of Peroxisome Proliferator Activated Receptor α in Pathogenesis of Colorectal Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(11): 1320-1324. doi: Copy

1.	Lee CH， Olson P， Hevener A， et al. PPARdelta regulates glucosemetabolism and insulin sensitivity[J]. Proc Natl Acad Sci U S A， 2006， 103(9)：3444-3449.
2.	Miles PD， Barak Y， He W， et al. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency[J]. J Clin Invest， 2000， 105(3)：287-292.
3.	Schoonjans K， Staels B， Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation[J]. Biochim Biophys Acta， 1996， 1302(2)：93-109.
4.	Theocharis S， Margeli A， Vielh P， et al. Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators[J]. Cancer Treat Rev， 2004， 30(6)：545-554.
5.	Peters JM， Aoyama T， Cattley RC， et al. Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver[J]. Carcinogenesis， 1998， 19(11)：1989-1994.
6.	Kitamura S， Miyazaki Y， Shinomura Y， et al. Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells[J]. Jpn J Cancer Res， 1999， 90(1)：75-80.
7.	Yang L， Zhang H， Zhou ZG， et al. Biological function and prognostic significance of peroxisome proliferator-activated receptor δ in rectal cancer[J]. Clin Cancer Res， 2011， 17(11)：3760-3770.
8.	Takayama O， Yamamoto H， Damdinsuren B， et al. Expression of PPARdelta in multistage carcinogenesis of the colorectum：implications of malignant cancer morphology[J]. Br J Cancer， 2006， 95(7)：889-895.
9.	杨烈，周总光. 结直肠癌发病机理的新位点——PPARδ[J]. 中国普外基础与临床杂志， 2006， 13(4)：484-486.
10.	Sher T， Yi HF， McBride OW， et al. cDNA cloning， chromosomalmapping， and functional characterization of the human peroxisomeproliferator activated receptor[J]. Biochemistry， 1993， 32(21)：5598-5604.
11.	Corton JC， Anderson SP， Stauber A. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome prolif-erators[J]. Annu Rev Pharmacol Toxicol， 2000， 40：491-518.
12.	Shahidi F， Miraliakbari H. Omega-3 (n-3) fatty acids in health and disease：Part 1—cardiovascular disease and cancer[J]. J Med Food， 2004， 7(4)：387-401.
13.	Braissant O， Foufelle F， Scotto C， et al. Differential expression of peroxisome proliferator-activated receptors (PPARs)：tissuedistribution of PPAR-alpha， -beta， and -gamma in the adult rat[J].Endocrinology， 1996， 137(1)：354-366.
14.	Mukherjee R， Jow L， Croston GE， et al. Identification， charac-terization， and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma 2 versus PPAR-gamma 1 and activation with retinoid X receptor agonists and anta-gonists[J]. J Biol Chem， 1997， 272(12)：8071-8076.
15.	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 receptor-alpha in humans：no alteration in adipose tissue of obese and NIDDM patients[J]. Diabetes， 1997， 46(8)：1319-1327.
16.	Huin C， Corriveau L， Bianchi A， et al. Differential expression of peroxisome proliferator-activated receptors (PPARs) in the developing human fetal digestive tract[J]. J Histochem Cytochem， 2000， 48(5)：603-611.
17.	Park JI， Kwak JY. The role of peroxisome proliferator-activated receptors in colorectal cancer[J]. PPAR Res， 2012， 2012， ArticleID 876418. http：//dx. doi. org/10. 1155/2012/876418.
18.	Barger PM， Browning AC， Garner AN， et al. p38 mitogen-acti-vated protein kinase activates peroxisome proliferator-activated receptor alpha：a potential role in the cardiac metabolic stress response[J]. J Biol Chem， 2001， 276(48)：44495-44501.
19.	Burns KA， Vanden Heuvel JP. Modulation of PPAR activity via phosphorylation[J]. Biochim Biophys Acta， 2007， 1771(8)：952-960.
20.	Eaden JA， Abrams KR， Mayberry JF. The risk of colorectalcancer in ulcerative colitis：a meta-analysis[J]. Gut， 2001， 48(4)：526-535.
21.	(6)：985-989.
22.	Tanaka T， Kohno H， Yoshitani S， et al. Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemicallyinduced colitis and formation of aberrant crypt foci in rats[J]. Cancer Res， 2001， 61(6)：2424-2428.
23.	Kohno H， Suzuki R， Sugie S， et al. Suppression of colitis-relatedmouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands[J]. BMC Cancer， 2005， 5：46. doi：10.1186/1471-2407-5-46.
24.	Matthiessen MW， Pedersen G， Albrektsen T， et al. Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas[J]. Scand J Gastroenterol， 2005， 40(2)：198-205.
25.	Mutoh M， Niho N， Wakabayashi K. Concomitant suppression of hyperlipidemia and intestinal polyp formation by increasing lipoprotein lipase activity in APC-deficient mice[J]. Biol Chem， 2006， 387(4)：381-385.
26.	Martinasso G， Oraldi M， Trombetta A， et al. Involvement of PPARs in cell proliferation and apoptosis in human colon cancer specimens and in normal and cancer cell lines[J]. PPAR Res， 2007， 2007：93416.
27.	Roberts RA， Chevalier S， Hasmall SC， et al. PPAR alpha and the regulation of cell division and apoptosis[J]. Toxicology， 2002， 181-182：167-170.
28.	Klaunig JE， Babich MA， Baetcke KP， et al. PPARalpha agonist-induced rodent tumors：modes of action and human relevance[J]. Crit Rev Toxicol， 2003， 33(6)：655-780.
29.	Ignacio Barrasa J， Olmo N， Pérez-Ramos P， et al. Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells[J]. Apoptosis， 2011， 16(10)：1054-1067.
30.	Barrasa JI， Santiago-Gómez A， Olmo N， et al. Resistance to butyrate impairs bile acid-induced apoptosis in human colon ade-nocarcinoma cells via up-regulation of Bcl-2 and inactivation of Bax[J]. Biochim Biophys Acta， 2012， 1823(12)：2201-2209.
31.	Makishima M， Okamoto AY， Repa JJ， et al. Identification of a nuclear receptor for bile acids[J]. Science， 1999， 284(5418)：1362-1365.
32.	Oshio H， Abe T， Onogawa T， et al. Peroxisome proliferator-activated receptor alpha activates cyclooxygenase-2 gene transcription through bile acid transport in human colorectal cancer cell lines[J]. J Gastroenterol， 2008， 43(7)：538-549.
33.	Bertagnolli MM. Chemoprevention of colorectal cancer withcyclooxygenase-2 inhibitors：two steps forward， one step back[J]. Lancet Oncol， 2007， 8(5)：439-443.
34.	Ikawa H， Kameda H， Kamitani H， et al. Effect of PPAR activators on cytokine-stimulated cyclooxygenase-2 expression in humancolorectal carcinoma cells[J]. Exp Cell Res， 2001， 267(1)：73-80.
35.	Lachal S， Ford J， Shulkes A， et al. PPARalpha agonists stimulate progastrin production in human colorectal carcinoma cells[J]. Regul Pept， 2004， 120(1-3)：243-251.
36.	Konturek PC， Bielanski W， Konturek SJ， et al. Progastrin and cyclooxygenase-2 in colorectal cancer[J]. Dig Dis Sci， 2002， 47(9)：1984-1991.
37.	Huin C， Schohn H， Hatier R， et al. Expression of peroxisome proliferator-activated receptors alpha and gamma in differentiatinghuman colon carcinoma Caco-2 cells[J]. Biol Cell， 2002， 94(1)：15-27.
38.	Varanasi U， Chu R， Huang Q， et al. Identification of a peroxisomeproliferator-responsive element upstream of the human peroxisomalfatty acyl coenzyme A oxidase gene[J]. J Biol Chem， 1996， 271(4)：2147-2155.
39.	Lauer C， Völkl A， Riedl S， et al. Impairment of peroxisomal biogenesis in human colon carcinoma[J]. Carcinogenesis， 1999，.
40.	Aung CS， Faddy HM， Lister EJ， et al. Isoform specific changes in PPAR alpha and beta in colon and breast cancer with differentiation[J]. Biochem Biophys Res Commun， 2006， 340(2)：656-660.
41.	Tong JL， Zhang CP， Nie F， et al. MicroRNA 506 regulates expr-ession of PPAR alpha in hydroxycamptothecin-resistant human colon cancer cells[J]. FEBS Lett， 2011， 585(22)：3560-3568.
42.	Watanabe M， Sowa Y， Yogosawa M， et al. Novel MEK inhibitortrametinib and other retinoblastoma gene (RB)-reactivating agentsenhance efficacy of 5-fluorouracil on human colon cancer cells[J]. Cancer Sci， 2013， 104(6)：687-693.
43.	Grabacka M， Pierzchalska M， Reiss K. Peroxisome proliferator activated receptor α ligands as anticancer drugs targeting mitocho-ndrial metabolism[J]. Curr Pharm Biotechnol， 2013， 14(3)：342-356.
44.	Camarero N， Mascaró C， Mayordomo C， et al. Ketogenic HMGCS2 is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer[J]. Mol Cancer Res， 2006， 4(9)：645-653.
45.	Sánchez-Aragó M， Chamorro M， Cuezva JM. Selection of cancercells with repressed mitochondria triggers colon cancer progression[J]. Carcinogenesis， 2010， 31(4)：567-576.
46.	Scatena R， Bottoni P， Giardina B. Mitochondria， PPARs， andcancer：Is receptor-independent action of PPAR agonists a key?[J]. PPAR Res， 2008， 2008：256251. doi：10.1155/2008/256251.

1. Lee CH， Olson P， Hevener A， et al. PPARdelta regulates glucosemetabolism and insulin sensitivity[J]. Proc Natl Acad Sci U S A， 2006， 103(9)：3444-3449.
2. Miles PD， Barak Y， He W， et al. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency[J]. J Clin Invest， 2000， 105(3)：287-292.
3. Schoonjans K， Staels B， Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation[J]. Biochim Biophys Acta， 1996， 1302(2)：93-109.
4. Theocharis S， Margeli A， Vielh P， et al. Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators[J]. Cancer Treat Rev， 2004， 30(6)：545-554.
5. Peters JM， Aoyama T， Cattley RC， et al. Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver[J]. Carcinogenesis， 1998， 19(11)：1989-1994.
6. Kitamura S， Miyazaki Y， Shinomura Y， et al. Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells[J]. Jpn J Cancer Res， 1999， 90(1)：75-80.
7. Yang L， Zhang H， Zhou ZG， et al. Biological function and prognostic significance of peroxisome proliferator-activated receptor δ in rectal cancer[J]. Clin Cancer Res， 2011， 17(11)：3760-3770.
8. Takayama O， Yamamoto H， Damdinsuren B， et al. Expression of PPARdelta in multistage carcinogenesis of the colorectum：implications of malignant cancer morphology[J]. Br J Cancer， 2006， 95(7)：889-895.
9. 杨烈，周总光. 结直肠癌发病机理的新位点——PPARδ[J]. 中国普外基础与临床杂志， 2006， 13(4)：484-486.
10. Sher T， Yi HF， McBride OW， et al. cDNA cloning， chromosomalmapping， and functional characterization of the human peroxisomeproliferator activated receptor[J]. Biochemistry， 1993， 32(21)：5598-5604.
11. Corton JC， Anderson SP， Stauber A. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome prolif-erators[J]. Annu Rev Pharmacol Toxicol， 2000， 40：491-518.
12. Shahidi F， Miraliakbari H. Omega-3 (n-3) fatty acids in health and disease：Part 1—cardiovascular disease and cancer[J]. J Med Food， 2004， 7(4)：387-401.
13. Braissant O， Foufelle F， Scotto C， et al. Differential expression of peroxisome proliferator-activated receptors (PPARs)：tissuedistribution of PPAR-alpha， -beta， and -gamma in the adult rat[J].Endocrinology， 1996， 137(1)：354-366.
14. Mukherjee R， Jow L， Croston GE， et al. Identification， charac-terization， and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma 2 versus PPAR-gamma 1 and activation with retinoid X receptor agonists and anta-gonists[J]. J Biol Chem， 1997， 272(12)：8071-8076.
15. 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 receptor-alpha in humans：no alteration in adipose tissue of obese and NIDDM patients[J]. Diabetes， 1997， 46(8)：1319-1327.
16. Huin C， Corriveau L， Bianchi A， et al. Differential expression of peroxisome proliferator-activated receptors (PPARs) in the developing human fetal digestive tract[J]. J Histochem Cytochem， 2000， 48(5)：603-611.
17. Park JI， Kwak JY. The role of peroxisome proliferator-activated receptors in colorectal cancer[J]. PPAR Res， 2012， 2012， ArticleID 876418. http：//dx. doi. org/10. 1155/2012/876418.
18. Barger PM， Browning AC， Garner AN， et al. p38 mitogen-acti-vated protein kinase activates peroxisome proliferator-activated receptor alpha：a potential role in the cardiac metabolic stress response[J]. J Biol Chem， 2001， 276(48)：44495-44501.
19. Burns KA， Vanden Heuvel JP. Modulation of PPAR activity via phosphorylation[J]. Biochim Biophys Acta， 2007， 1771(8)：952-960.
20. Eaden JA， Abrams KR， Mayberry JF. The risk of colorectalcancer in ulcerative colitis：a meta-analysis[J]. Gut， 2001， 48(4)：526-535.
21. (6)：985-989.
22. Tanaka T， Kohno H， Yoshitani S， et al. Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemicallyinduced colitis and formation of aberrant crypt foci in rats[J]. Cancer Res， 2001， 61(6)：2424-2428.
23. Kohno H， Suzuki R， Sugie S， et al. Suppression of colitis-relatedmouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands[J]. BMC Cancer， 2005， 5：46. doi：10.1186/1471-2407-5-46.
24. Matthiessen MW， Pedersen G， Albrektsen T， et al. Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas[J]. Scand J Gastroenterol， 2005， 40(2)：198-205.
25. Mutoh M， Niho N， Wakabayashi K. Concomitant suppression of hyperlipidemia and intestinal polyp formation by increasing lipoprotein lipase activity in APC-deficient mice[J]. Biol Chem， 2006， 387(4)：381-385.
26. Martinasso G， Oraldi M， Trombetta A， et al. Involvement of PPARs in cell proliferation and apoptosis in human colon cancer specimens and in normal and cancer cell lines[J]. PPAR Res， 2007， 2007：93416.
27. Roberts RA， Chevalier S， Hasmall SC， et al. PPAR alpha and the regulation of cell division and apoptosis[J]. Toxicology， 2002， 181-182：167-170.
28. Klaunig JE， Babich MA， Baetcke KP， et al. PPARalpha agonist-induced rodent tumors：modes of action and human relevance[J]. Crit Rev Toxicol， 2003， 33(6)：655-780.
29. Ignacio Barrasa J， Olmo N， Pérez-Ramos P， et al. Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells[J]. Apoptosis， 2011， 16(10)：1054-1067.
30. Barrasa JI， Santiago-Gómez A， Olmo N， et al. Resistance to butyrate impairs bile acid-induced apoptosis in human colon ade-nocarcinoma cells via up-regulation of Bcl-2 and inactivation of Bax[J]. Biochim Biophys Acta， 2012， 1823(12)：2201-2209.
31. Makishima M， Okamoto AY， Repa JJ， et al. Identification of a nuclear receptor for bile acids[J]. Science， 1999， 284(5418)：1362-1365.
32. Oshio H， Abe T， Onogawa T， et al. Peroxisome proliferator-activated receptor alpha activates cyclooxygenase-2 gene transcription through bile acid transport in human colorectal cancer cell lines[J]. J Gastroenterol， 2008， 43(7)：538-549.
33. Bertagnolli MM. Chemoprevention of colorectal cancer withcyclooxygenase-2 inhibitors：two steps forward， one step back[J]. Lancet Oncol， 2007， 8(5)：439-443.
34. Ikawa H， Kameda H， Kamitani H， et al. Effect of PPAR activators on cytokine-stimulated cyclooxygenase-2 expression in humancolorectal carcinoma cells[J]. Exp Cell Res， 2001， 267(1)：73-80.
35. Lachal S， Ford J， Shulkes A， et al. PPARalpha agonists stimulate progastrin production in human colorectal carcinoma cells[J]. Regul Pept， 2004， 120(1-3)：243-251.
36. Konturek PC， Bielanski W， Konturek SJ， et al. Progastrin and cyclooxygenase-2 in colorectal cancer[J]. Dig Dis Sci， 2002， 47(9)：1984-1991.
37. Huin C， Schohn H， Hatier R， et al. Expression of peroxisome proliferator-activated receptors alpha and gamma in differentiatinghuman colon carcinoma Caco-2 cells[J]. Biol Cell， 2002， 94(1)：15-27.
38. Varanasi U， Chu R， Huang Q， et al. Identification of a peroxisomeproliferator-responsive element upstream of the human peroxisomalfatty acyl coenzyme A oxidase gene[J]. J Biol Chem， 1996， 271(4)：2147-2155.
39. Lauer C， Völkl A， Riedl S， et al. Impairment of peroxisomal biogenesis in human colon carcinoma[J]. Carcinogenesis， 1999，.
40. Aung CS， Faddy HM， Lister EJ， et al. Isoform specific changes in PPAR alpha and beta in colon and breast cancer with differentiation[J]. Biochem Biophys Res Commun， 2006， 340(2)：656-660.
41. Tong JL， Zhang CP， Nie F， et al. MicroRNA 506 regulates expr-ession of PPAR alpha in hydroxycamptothecin-resistant human colon cancer cells[J]. FEBS Lett， 2011， 585(22)：3560-3568.
42. Watanabe M， Sowa Y， Yogosawa M， et al. Novel MEK inhibitortrametinib and other retinoblastoma gene (RB)-reactivating agentsenhance efficacy of 5-fluorouracil on human colon cancer cells[J]. Cancer Sci， 2013， 104(6)：687-693.
43. Grabacka M， Pierzchalska M， Reiss K. Peroxisome proliferator activated receptor α ligands as anticancer drugs targeting mitocho-ndrial metabolism[J]. Curr Pharm Biotechnol， 2013， 14(3)：342-356.
44. Camarero N， Mascaró C， Mayordomo C， et al. Ketogenic HMGCS2 is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer[J]. Mol Cancer Res， 2006， 4(9)：645-653.
45. Sánchez-Aragó M， Chamorro M， Cuezva JM. Selection of cancercells with repressed mitochondria triggers colon cancer progression[J]. Carcinogenesis， 2010， 31(4)：567-576.
46. Scatena R， Bottoni P， Giardina B. Mitochondria， PPARs， andcancer：Is receptor-independent action of PPAR agonists a key?[J]. PPAR Res， 2008， 2008：256251. doi：10.1155/2008/256251.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Role of Peroxisome Proliferator Activated Receptor α in Pathogenesis of Colorectal Cancer

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