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Peroxisome proliferator-activated receptor-γ and esophageal cancer
EDITORIAL Peroxisome proliferator-activated receptor-␥ and esophageal cancer Abbreviations: DNA ⫽ deoxyribonucleic acid; 15d-PGJ2 ⫽ 15-deoxy-⌬ prostaglandin J2; mRNA ⫽ messenger ribonucleic acid; PPAR ⫽ peroxisome proliferator-activated receptor; PPRE ⫽ peroxisome proliferator-responsive element
P
eroxisome proliferator-activated receptor is a member of the nuclear hormone receptor superfamily of transcription factors. Three distinct isoforms of PPARs, which are encoded by separate genes, have been identified so far: PPAR-␣, PPAR-␦ (also known as PPAR- or NUC-1) and PPAR-␥. Among these isoforms, PPAR-␣ was discovered first, in 1990, as a mediator of peroxisome proliferation which occurs in response to a variety of pharmacological and nutritional triggers in rodents. However, because subsequent studies revealed important biological functions of PPAR isoforms other than peroxisome proliferation, medical interest in PPAR, especially PPAR-␥, has been growing rapidly. PPAR-␥ has two subtypes, PPAR-␥1 and PPAR-␥2, which are derived from alterative promoter usage and splicing. In human beings, PPAR-␥2 has 30 extra amino acids at the Nterminus. PPAR-␥2 is exclusively expressed in adipocytes and is a potent regulator of adipocyte differentiation.1 PPAR-␥1 is also expressed at high levels in adipocytes, but the expression of PPAR-␥1 is found in several other tissues, including gastrointestinal epithelial cells. Naturally occurring fatty acids and fatty-acid derivatives (including eicosanoids) are known to act as ligands for each PPAR isoform.2,3 Although a variety of fatty acids and fatty-acid metabolites are potential ligands for PPAR-␥, 15d-PGJ2, a
From the Department of Gastroenterology, Dokkyo University School of Medicine. Submitted for publication March 20, 2002; accepted March 25, 2002. Reprint requests: Akira Terano, MD, PhD, Department of Gastroenterology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan 321-0293; e-mail: [email protected]. Copyright © 2002 by Mosby, Inc. All rights reserved. 0022-2143/2002 $35.00 ⫹ 0 5/1/125054 doi:10.1067/mlc.2002.125054
4
metabolite of prostaglandin D2, is assumed to be the most probable physiological ligand for PPAR-␥.4,5 It is also known that thiazolidinediones, synthetic antidiabetic agents such as troglitazone and pioglitazone, are specific pharmacological ligands for PPAR-␥.6 On activation (ligand binding), PPAR-␥ forms a heterodimer with a retinoid X receptor similar to other nuclear receptors and regulates the transcription of target genes by binding to the unique DNA element designated PPREs. As mentioned earlier, several studies have revealed that PPAR-␥ is a critical transcription factor in adipocyte differentiation. Consistent with this, PPREs are found in the promoter regions of the genes involved in fatty-acid metabolism and energy balance, including adipocyte P2, phosphoenol pyruvate carboxykinase, acyl coenzyme A synthetase, fatty-acid transport protein-1, and lipoprotein lipase. PPAR-␥ knockout mice showed more direct evidence of the involvement of PPAR-␥ in adipocyte differentiation: Adipose tissue is completely absent in PPAR-␥ ⫺/⫺ mice and significantly decreased in PPAR-␥ ⫹/⫺ mice.7,8 Recent studies have shown the expression (or increased expression) of PPAR-␥ in a wide range of cells from human cancers, including liposarcoma, breast cancer, prostate cancer, colorectal cancer, non-smallcell lung cancer, pancreatic cancer, bladder cancer, and gastric cancer cells. In most in vitro studies employing PPAR-␥-expressing cancer cell lines, activation of PPAR-␥ has been found to inhibit tumor cell growth.2 Further, it has been reported that PPAR-␥ ligands induce apoptosis in several cell types, such as macrophages, breast-cancer cells, prostate-cancer cells, nonsmall-cell lung cancer cells, and colon-cancer cells. It is also interesting that mutations of the PPAR-␥ gene have been identified in some colon cancers.9 PPAR-␥ is likely an important negative regulator of cell growth and inducer of apoptosis. For this reason, PPAR-␥ ligands may be promising agents in the treatment and, perhaps, the prevention of cancers. Mueller et al10
J Lab Clin Med Volume 140, Number 1
recently reported that in patients with advanced prostate caner, oral administration of troglitazone resulted in an unexpectedly high incidence of prolonged stabilization of prostate-specific antigen, a tumor maker for prostate cancer. In this issue of the Journal, Rumi et al report the effect of PPAR-␥ ligands on esophageal-cancer cells. They show high expression of PPAR-␥ mRNA and PPAR␥ proteins in esophageal squamous cancer cell lines T.T, T.Tn, and EC-GI-10, and they demonstrate that PPAR-␥ ligands troglitazone and 15d-PGJ2 suppress the growth response of these esophageal-cancer cells in a dose-dependent manner. This report seems to be the first demonstration that PPAR-␥ activation leads to the suppression of human esophageal-cancer cell growth. They also examine the effect of PPAR-␥ ligands on cell-cycle-regulatory proteins and reveal that PPAR-␥ ligand-induced growth inhibition is associated with an increased level of cyclin-dependent kinase inhibitors p27, p21, and p18. The incidence of esophageal cancer has increased in recent decades, and it is still one of the most lethal malignancies of the gastrointestinal tract. The overall 5-year survival in patients suitable for surgery ranges from 5% to 20%. For this reason, the results of the study by Rumi et al give us hope that novel therapeutic approach for esophageal cancers will be developed with agents that activate tumor-cell PPAR-␥. Further studies will be required to evaluate clinical usefulness of PPAR-␥ ligands (thiazolidinediones) in the control of esophageal cancers. It may be also important to evaluate the expression of PPAR-␥ and the effect of PPAR-␥ ligands on adenocarcinoma of the esophagus, the incidence of which is increasing rapidly. Some controversy still remains with regard to the anticancer action of thiazolidinediones. For example, although in vitro studies have shown a growth-suppressive effect of PPAR-␥ ligands on colorectal-cancer cells, application of thiazolidinediones to APCMin mice (an animal model of familial adenomatous polyposis of the colon) has been reported to increase the size and number of colon polyps.11,12 Therefore we should know the functions of PPAR-␥ in nonadipose tissues in
Editorial
5
more detail and should carefully assess the clinical usefulness of PPAR-␥ ligands in the treatment of cancer, including esophageal cancers. TADAHITO SHIMADA and AKIRA TERANO Tochigi, Japan
REFERENCES
1. MacDougald OA, Lane MD. Transcriptional regulation of gene expression during adipocyte differentiation. Annu Rev Biochem 1995;64:345-73. 2. Fajas L, Debril MB, Auwerx J. Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis. J Mol Endocrinol 2001;27:1-9. 3. Corton JC, Anderson SP, Stauber A. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. Annu Rev Pharmacol Toxicol 2000;40:491-518. 4. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 1995; 83:803-12. 5. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995;83:813-9. 6. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995;270:12953-6. 7. Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, et al. PPAR gamma mediates high-fat-diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999;4: 597-609. 8. Miles PD, Barak Y, He W, Evans RM, Olefsky JM. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest 2000;105:287-92. 9. Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, et al. Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell 1999;3:799-804. 10. Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS, et al. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci U S A 2000;97:10990-5. 11. Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, et al. Activation of the peroxisome proliferatoractivated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/⫹ mice. Nat Med 1998;4:1053-7. 12. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, et al. Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 1998;4:1058-61.
P
eroxisome proliferator-activated receptor is a member of the nuclear hormone receptor superfamily of transcription factors. Three distinct isoforms of PPARs, which are encoded by separate genes, have been identified so far: PPAR-␣, PPAR-␦ (also known as PPAR- or NUC-1) and PPAR-␥. Among these isoforms, PPAR-␣ was discovered first, in 1990, as a mediator of peroxisome proliferation which occurs in response to a variety of pharmacological and nutritional triggers in rodents. However, because subsequent studies revealed important biological functions of PPAR isoforms other than peroxisome proliferation, medical interest in PPAR, especially PPAR-␥, has been growing rapidly. PPAR-␥ has two subtypes, PPAR-␥1 and PPAR-␥2, which are derived from alterative promoter usage and splicing. In human beings, PPAR-␥2 has 30 extra amino acids at the Nterminus. PPAR-␥2 is exclusively expressed in adipocytes and is a potent regulator of adipocyte differentiation.1 PPAR-␥1 is also expressed at high levels in adipocytes, but the expression of PPAR-␥1 is found in several other tissues, including gastrointestinal epithelial cells. Naturally occurring fatty acids and fatty-acid derivatives (including eicosanoids) are known to act as ligands for each PPAR isoform.2,3 Although a variety of fatty acids and fatty-acid metabolites are potential ligands for PPAR-␥, 15d-PGJ2, a
From the Department of Gastroenterology, Dokkyo University School of Medicine. Submitted for publication March 20, 2002; accepted March 25, 2002. Reprint requests: Akira Terano, MD, PhD, Department of Gastroenterology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan 321-0293; e-mail: [email protected]. Copyright © 2002 by Mosby, Inc. All rights reserved. 0022-2143/2002 $35.00 ⫹ 0 5/1/125054 doi:10.1067/mlc.2002.125054
4
metabolite of prostaglandin D2, is assumed to be the most probable physiological ligand for PPAR-␥.4,5 It is also known that thiazolidinediones, synthetic antidiabetic agents such as troglitazone and pioglitazone, are specific pharmacological ligands for PPAR-␥.6 On activation (ligand binding), PPAR-␥ forms a heterodimer with a retinoid X receptor similar to other nuclear receptors and regulates the transcription of target genes by binding to the unique DNA element designated PPREs. As mentioned earlier, several studies have revealed that PPAR-␥ is a critical transcription factor in adipocyte differentiation. Consistent with this, PPREs are found in the promoter regions of the genes involved in fatty-acid metabolism and energy balance, including adipocyte P2, phosphoenol pyruvate carboxykinase, acyl coenzyme A synthetase, fatty-acid transport protein-1, and lipoprotein lipase. PPAR-␥ knockout mice showed more direct evidence of the involvement of PPAR-␥ in adipocyte differentiation: Adipose tissue is completely absent in PPAR-␥ ⫺/⫺ mice and significantly decreased in PPAR-␥ ⫹/⫺ mice.7,8 Recent studies have shown the expression (or increased expression) of PPAR-␥ in a wide range of cells from human cancers, including liposarcoma, breast cancer, prostate cancer, colorectal cancer, non-smallcell lung cancer, pancreatic cancer, bladder cancer, and gastric cancer cells. In most in vitro studies employing PPAR-␥-expressing cancer cell lines, activation of PPAR-␥ has been found to inhibit tumor cell growth.2 Further, it has been reported that PPAR-␥ ligands induce apoptosis in several cell types, such as macrophages, breast-cancer cells, prostate-cancer cells, nonsmall-cell lung cancer cells, and colon-cancer cells. It is also interesting that mutations of the PPAR-␥ gene have been identified in some colon cancers.9 PPAR-␥ is likely an important negative regulator of cell growth and inducer of apoptosis. For this reason, PPAR-␥ ligands may be promising agents in the treatment and, perhaps, the prevention of cancers. Mueller et al10
J Lab Clin Med Volume 140, Number 1
recently reported that in patients with advanced prostate caner, oral administration of troglitazone resulted in an unexpectedly high incidence of prolonged stabilization of prostate-specific antigen, a tumor maker for prostate cancer. In this issue of the Journal, Rumi et al report the effect of PPAR-␥ ligands on esophageal-cancer cells. They show high expression of PPAR-␥ mRNA and PPAR␥ proteins in esophageal squamous cancer cell lines T.T, T.Tn, and EC-GI-10, and they demonstrate that PPAR-␥ ligands troglitazone and 15d-PGJ2 suppress the growth response of these esophageal-cancer cells in a dose-dependent manner. This report seems to be the first demonstration that PPAR-␥ activation leads to the suppression of human esophageal-cancer cell growth. They also examine the effect of PPAR-␥ ligands on cell-cycle-regulatory proteins and reveal that PPAR-␥ ligand-induced growth inhibition is associated with an increased level of cyclin-dependent kinase inhibitors p27, p21, and p18. The incidence of esophageal cancer has increased in recent decades, and it is still one of the most lethal malignancies of the gastrointestinal tract. The overall 5-year survival in patients suitable for surgery ranges from 5% to 20%. For this reason, the results of the study by Rumi et al give us hope that novel therapeutic approach for esophageal cancers will be developed with agents that activate tumor-cell PPAR-␥. Further studies will be required to evaluate clinical usefulness of PPAR-␥ ligands (thiazolidinediones) in the control of esophageal cancers. It may be also important to evaluate the expression of PPAR-␥ and the effect of PPAR-␥ ligands on adenocarcinoma of the esophagus, the incidence of which is increasing rapidly. Some controversy still remains with regard to the anticancer action of thiazolidinediones. For example, although in vitro studies have shown a growth-suppressive effect of PPAR-␥ ligands on colorectal-cancer cells, application of thiazolidinediones to APCMin mice (an animal model of familial adenomatous polyposis of the colon) has been reported to increase the size and number of colon polyps.11,12 Therefore we should know the functions of PPAR-␥ in nonadipose tissues in
Editorial
5
more detail and should carefully assess the clinical usefulness of PPAR-␥ ligands in the treatment of cancer, including esophageal cancers. TADAHITO SHIMADA and AKIRA TERANO Tochigi, Japan
REFERENCES
1. MacDougald OA, Lane MD. Transcriptional regulation of gene expression during adipocyte differentiation. Annu Rev Biochem 1995;64:345-73. 2. Fajas L, Debril MB, Auwerx J. Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis. J Mol Endocrinol 2001;27:1-9. 3. Corton JC, Anderson SP, Stauber A. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. Annu Rev Pharmacol Toxicol 2000;40:491-518. 4. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 1995; 83:803-12. 5. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995;83:813-9. 6. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995;270:12953-6. 7. Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, et al. PPAR gamma mediates high-fat-diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999;4: 597-609. 8. Miles PD, Barak Y, He W, Evans RM, Olefsky JM. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest 2000;105:287-92. 9. Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, et al. Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell 1999;3:799-804. 10. Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS, et al. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci U S A 2000;97:10990-5. 11. Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, et al. Activation of the peroxisome proliferatoractivated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/⫹ mice. Nat Med 1998;4:1053-7. 12. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, et al. Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 1998;4:1058-61.