Proline Oxidase, a Proapoptotic Gene, Is Induced by Troglitazone

Proline oxidase (POX) is a redox enzyme localized in the mitochondrial inner membrane. We and others have shown that POX is a p53-induced gene that can mediate apoptosis through generation of reactive oxygen species (ROS). The peroxisome proliferator-activated receptor γ (PPARγ) ligand troglitazone was found to activate the POX promoter in colon cancer cells. PPARγ ligands have been reported to induce apoptosis in a variety of cancer cells. In HCT116 cells expressing a wild-type PPARγ, troglitazone enhanced the binding of PPARγ to PPAR-responsive element in the POX promoter and increased endogenous POX expression. Blocking of PPARγ activation either by antagonist GW9662 or deletion of PPAR-responsive element in the POX promoter only partially decreased the POX promoter activation in response to troglitazone, indicating also the involvement of PPARγ-independent mechanisms. Further, troglitazone also induced p53 protein expression in HCT116 cells, which may be the possible mechanism for PPARγ-independent POX activation, since POX has been shown to be a downstream mediator in p53-induced apoptosis. In HCT15 cells, with both mutant p53 and mutant PPARγ, there was no effect of troglitazone on POX activation, whereas in HT29 cells, with a mutant p53 and wild type PPARγ, increased activation was observed by ligand stimulation, indicating that both PPARγ-dependent and -independent mechanisms are involved in the troglitazone-induced POX expression. A time- and dose-dependent increase in POX catalytic activity was obtained in HCT116 cells treated with troglitazone with a concomitant increase in the production of intracellular ROS. Our results suggest that the induction of apoptosis by troglitazone may, at least in part, be mediated by targeting POX gene expression for generation of ROS by POX both by PPARγ-dependent and -independent mechanisms.

• Publication year

  2006

• Venue

  Journal of Biological Chemistry

• Publication date

  2006-01-27

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M507867200PMID 16303758
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Prostaglandin D(2) and J(2) induce apoptosis in human leukemia cells via activation of the caspase 3 cascade and production of reactive oxygen species.

  2005cited by this paper
• Prostaglandin D2 and J2 induce apoptosis in human leukemia cells via activation of the caspase 3 cascade and production of reactive oxygen species

  2005cited by this paper
• MnSOD inhibits proline oxidase-induced apoptosis in colorectal cancer cells.

  2005cited by this paper
• Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression in non-small-cell lung cancer.

  2004cited by this paper
• Beginnings of a signal-transduction pathway for bioenergetic control of cell survival.

  2004cited by this paper
• Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators.

  2004cited by this paper
• PPARs and the complex journey to obesity

  2004cited by this paper
• Peroxisome-proliferator-activated receptors and cancers: complex stories

  2004cited by this paper
• Peroxisome proliferator-activated receptor-γ ligands as cell-cycle modulators

  2004cited by this paper
• Peroxisome proliferator-activated receptor-γ activation inhibits tumor progression in non-small-cell lung cancer

  2004cited by this paper
• Troglitazone Acts on Cellular pH and DNA Synthesis through a Peroxisome Proliferator-Activated Receptor γ-Independent Mechanism in Breast Cancer-Derived Cell Lines

  2004cited by this paper
• Glitazones Differentially Regulate Primary Astrocyte and Glioma Cell Survival

  2004cited by this paper
• Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists.

  2004cited by this paper
• Troglitazone inhibits cyclin D1 expression and cell cycling independently of PPARgamma in normal mouse skin keratinocytes.

  2004cited by this paper
• Induction of differentiation and peroxisome proliferator-activated receptor γ expression in colon cancer cell lines by troglitazone

  2004cited by this paper
• Antineoplastic effects of peroxisome proliferatoractivated receptor γ agonists

  2004cited by this paper
• PPAR gamma ligand-induced apoptosis through a p53-dependent mechanism in human gastric cancer cells.

  2003cited by this paper
• Original Articles: Liver Biology and PathobiologyPPARγ ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21WAF1/Cip1 pathway☆

  2003cited by this paper
• Thiazolidinediones inhibit growth of gastrointestinal, biliary, and pancreatic adenocarcinoma cells through activation of the peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha pathway.

  2003cited by this paper
• Peroxisome proliferator-activated receptor gamma-mediated differentiation: a mutation in colon cancer cells reveals divergent and cell type-specific mechanisms.

  2003cited by this paper
• PPARγ ligand‐induced apoptosis through a p53‐dependent mechanism in human gastric cancer cells

  2003cited by this paper
• Proline Oxidase Induces Apoptosis in Tumor Cells, and Its Expression Is Frequently Absent or Reduced in Renal Carcinomas*

  2003cited by this paper
• Troglitazone but not rosiglitazone induces G1 cell cycle arrest and apoptosis in human and rat hepatoma cell lines.

  2003cited by this paper
• Mitochondrial reactive oxygen species in cell death signaling.

  2002cited by this paper
• Characteristics of the peroxisome proliferator activated receptor γ (PPARγ) ligand induced apoptosis in colon cancer cells

  2002cited by this paper
• Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662.

  2002cited by this paper
• PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth.

  2001cited by this paper
• 15-deoxy-Delta 12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors.

  2001cited by this paper
• Organelle-specific initiation of cell death pathways

  2001cited by this paper
• Cyclopentenone Prostaglandins as Potential Inducers of Intracellular Oxidative Stress*

  2001cited by this paper
• Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species.

  2001cited by this paper
• Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells.

  2001cited by this paper
• Target genes of peroxisome proliferator-activated receptor gamma in colorectal cancer cells.

  2001cited by this paper
• Target Genes of Peroxisome Proliferator-activated Receptor γ in Colorectal Cancer Cells*

  2001cited by this paper
• PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth*

  2001cited by this paper
• Differential gene expression in p53-mediated apoptosis-resistant vs. apoptosis-sensitive tumor cell lines.

  2000cited by this paper
• Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells.

  2000cited by this paper
• The PPARs: from orphan receptors to drug discovery.

  2000cited by this paper
• Mitochondrial role in life and death of the cell.

  2000cited by this paper
• Roles of PPARs in health and disease

  2000cited by this paper
• Peroxisome proliferator-activated receptors: nuclear control of metabolism.

  1999cited by this paper
• Loss-of-function mutations in PPAR gamma associated with human colon cancer.

  1999cited by this paper
• Signal transduction by reactive oxygen species in non‐phagocytic cells

  1999cited by this paper
• Peroxisome Proliferator‐activated Receptor γ Induces Growth Arrest and Differentiation Markers of Human Colon Cancer Cells

  1999cited by this paper
• Loss-of-Function Mutations in PPARγ Associated with Human Colon Cancer

  1999cited by this paper
• Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice.

  1998cited by this paper
• Activation of PPARgamma leads to inhibition of anchorage-independent growth of human colorectal cancer cells.

  1998cited by this paper
• Activation of PPARγ leads to inhibition of anchorage-independent growth of human colorectal cancer cells

  1998cited by this paper
• Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo.

  1998cited by this paper
• Differentiation and reversal of malignant changes in colon cancer through PPARγ

  1998cited by this paper
• de la Chapelle, A.

  1997cited by this paper
• A model for p53-induced apoptosis

  1997cited by this paper
• Purified human erythrocyte pyrroline-5-carboxylate reductase. Preferential oxidation of NADPH.

  1989cited by this paper
• Stimulation of phosphoribosyl pyrophosphate and purine nucleotide production by pyrroline 5-carboxylate in human erythrocytes.

  1988cited by this paper
• Catalytic transfer of hydride ions from NADPH to oxygen by the interconversions of proline and delta 1-pyrroline-5-carboxylate.

  1986cited by this paper
• The regulatory functions of proline and pyrroline-5-carboxylic acid.

  1985cited by this paper
• Transfer of reducing equivalents into mitochondria by the interconversions of proline and delta 1-pyrroline-5-carboxylate.

  1983cited by this paper

• Proline metabolism reprogramming in cancer reveals the regulation of PRODH/POX as target.

  2026cites this paper
• Jujuboside B Induces Ferroptosis and Overcomes Radioresistance Through the PPARγ‐ATF3‐Gpx4 Signaling Pathway in Non‐Small Cell Lung Cancer

  2025cites this paper
• Multifunctionality and Possible Medical Application of the BPC 157 Peptide—Literature and Patent Review

  2025cites this paper
• Proline Metabolism in Cancer: Emerging Roles in Redox Homeostasis and Therapeutic Opportunities

  2025cites this paper
• Integrated transcriptomics and metabolomics study of embryonic breast muscle of Jiaji ducks

  2024cites this paper
• Proline Dehydrogenase (PRODH) Is Expressed in Lung Adenocarcinoma and Modulates Cell Survival and 3D Growth by Inducing Cellular Senescence

  2024cites this paper
• Liver Metabolic Dysregulation Induced by Polypropylene Nano- and Microplastics in Nile Tilapia Using Internal Extractive Electrospray Ionization Mass Spectrometry.

  2023cites this paper
• Can proline dehydrogenase—a key enzyme involved in proline metabolism—be a novel target for cancer therapy?

  2023cites this paper
• Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis

  2022cites this paper
• Proline Metabolism in Neurological and Psychiatric Disorders

  2022cites this paper
• NSAIDs Induce Proline Dehydrogenase/Proline Oxidase-Dependent and Independent Apoptosis in MCF7 Breast Cancer Cells

  2022cites this paper
• Oncogenic viral infection and amino acid metabolism in cancer progression: Molecular insights and clinical implications.

  2022cites this paper
• P5C as an Interface of Proline Interconvertible Amino Acids and Its Role in Regulation of Cell Survival and Apoptosis

  2021cites this paper
• Proline dehydrogenase in cancer: apoptosis, autophagy, nutrient dependency and cancer therapy

  2021cites this paper
• Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

  2021cites this paper
• Geniposide Ameliorates Liver Fibrosis Through Reducing Oxidative Stress and Inflammatory Respose, Inhibiting Apoptosis and Modulating Overall Metabolism

  2021cites this paper
• Understanding the Role of Estrogen Receptor Status in PRODH/POX-Dependent Apoptosis/Survival in Breast Cancer Cells

  2021cites this paper
• Mitochondrial Tumor Suppressors—The Energetic Enemies of Tumor Progression

  2021cites this paper
• Proline oxidase silencing inhibits p53-dependent apoptosis in MCF-7 breast cancer cells

  2021cites this paper
• Collagen metabolism as a regulator of proline dehydrogenase/proline oxidase-dependent apoptosis/autophagy

  2021influential citation
• Troglitazone-Induced PRODH/POX-Dependent Apoptosis Occurs in the Absence of Estradiol or ERβ in ER-Negative Breast Cancer Cells

  2021influential citation
• Activation of proline metabolism maintains ATP levels during cocaine-induced polyADP-ribosylation

  2021cites this paper
• Proline metabolism in cancer

  2021cites this paper
• The Janus-like role of proline metabolism in cancer

  2020cites this paper
• A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells: the implication of proline oxidase and peroxisome proliferator-activated receptor

  2020cites this paper
• Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies

  2020cites this paper
• Overexpression of Prolidase Induces Autophagic Death in MCF-7 Breast Cancer Cells.

  2020cites this paper
• HDAC inhibitors induce proline dehydrogenase (POX) transcription and anti-apoptotic autophagy in triple negative breast cancer.

  2019cites this paper
• Receptory aktywowane przez proliferatory peroksysomów w procesie nowotworzenia - fakty i kontrowersje

  2018cites this paper
• Proline oxidase silencing induces proline-dependent pro-survival pathways in MCF-7 cells

  2018cites this paper
• Trimming proline dehydrogenase : protein and cofactor minimization

  2017cites this paper
• Functional Consequences of Intracellular Proline Levels Manipulation Affecting PRODH/POX–Dependent Pro-Apoptotic Pathways in a Novel in Vitro Cell Culture Model

  2017cites this paper
• Structural Biology of Proline Catabolic Enzymes

  2017cites this paper
• Proline Metabolism in Cell Regulation and Cancer Biology: Recent Advances and Hypotheses

  2017cites this paper
• Untargeted metabolomics analysis of adipogenic transformation in OP9‐DL1 cells using liquid chromatography‐mass spectrometry: Implications for thymic adipogenesis

  2017cites this paper
• Pharmacoinformatics and molecular docking studies reveal potential novel Proline Dehydrogenase (PRODH) compounds for Schizophrenia inhibition

  2016cites this paper
• Prolidase‐proline dehydrogenase/proline oxidase‐collagen biosynthesis axis as a potential interface of apoptosis/autophagy

  2016cites this paper
• 18O-Tracer Metabolomics Reveals Protein Turnover and CDP-Choline Cycle Activity in Differentiating 3T3-L1 Pre-Adipocytes

  2016cites this paper
• Protective Effects of Turbinaria ornata and Padina pavonia against Azoxymethane‐Induced Colon Carcinogenesis through Modulation of PPAR Gamma, NF‐κB and Oxidative Stress

  2015cites this paper
• Ornithine-δ-Aminotransferase Inhibits Neurogenesis During Xenopus Embryonic Development.

  2015cites this paper
• MicroRNAs in adrenal tumors: relevance for pathogenesis, diagnosis, and therapy

  2015cites this paper
• Proline Oxidase (POX) as A Target for Cancer Therapy.

  2015cites this paper
• A Novel Role of Proline Oxidase in HIV-1 Envelope Glycoprotein-induced Neuronal Autophagy*

  2015cites this paper
• Impact des ligands de PPARs, et leurs dérivés, sur les cellules cancéreuses coliques humaines : modifications des statuts redox et glycolytique

  2014cites this paper
• Determination of common urine substances as an assay for improving prostate carcinoma diagnostics.

  2014cites this paper
• Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients.

  2014cites this paper
• Large-Scaled Metabolic Profiling of Human Dermal Fibroblasts Derived from Pseudoxanthoma Elasticum Patients and Healthy Controls

  2014cites this paper
• Proline: Metabolic Sensing and Parametabolic Regulation

  2014cites this paper
• The aryl hydrocarbon receptor nuclear translocator (ARNT) modulates the antioxidant response in AML cells.

  2013cites this paper
• MiRNA and Proline Metabolism in Cancer

  2013cites this paper
• Proline Mechanisms of Stress Survival

  2013cites this paper
• Bridging epigenetics and metabolism

  2013cites this paper
• Proline metabolism and cancer.

  2012cites this paper
• Proline oxidase promotes tumor cell survival in hypoxic tumor microenvironments.

  2012influential citation
• Proline dehydrogenase is essential for proline protection against hydrogen peroxide-induced cell death.

  2012cites this paper
• Proline dehydrogenase: a key enzyme in controlling cellular homeostasis.

  2012cites this paper
• Metabolomic analysis of dynamic response and drug resistance of gastric cancer cells to 5-fluorouracil

  2012cites this paper
• Unique structural features and sequence motifs of proline utilization A (PutA).

  2012cites this paper
• Role of apoptosis-inducing factor, proline dehydrogenase, and NADPH oxidase in apoptosis and oxidative stress.

  2012cites this paper
• Crystal structures and kinetics of monofunctional proline dehydrogenase provide insight into substrate recognition and conformational changes associated with flavin reduction and product release.

  2012cites this paper
• The Proline Regulatory Axis and Cancer

  2012cites this paper
• Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC

  2012cites this paper
• Proline dehydrogenase (oxidase) in cancer

  2012cites this paper
• Identification and functional activation of peroxisome proliferator-activated receptor in human upper aerodigestive cancer

  2012cites this paper
• MECANISMOS DE TOXICIDADE DA PROLINA E EFEITOS DA ADMINISTRAÇÃO DE CREATINA E PIRUVATO EM MODELO DE HIPERPROLINEMIA MATERNA DE RATAS

  2012cites this paper
• Enhanced PPAR-gamma expression may correlate with the development of Barrett's esophagus and esophageal adenocarcinoma.

  2011cites this paper
• The Uniqueness of the Trypanosoma cruzi Mitochondrion: Opportunities to Target New Drugs Against Chagas Disease

  2011cites this paper
• The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

  2011cites this paper
• Rhodiola‐induced inhibition of adipogenesis involves antioxidant enzyme response associated with pentose phosphate pathway

  2011cites this paper
• Troglitazone induced apoptosis via PPARγ activated POX-induced ROS formation in HT29 cells.

  2011cites this paper
• Peroxisome proliferator-activated receptor γ and colorectal cancer.

  2010cites this paper
• MicroRNA-23b* targets proline oxidase, a mitochondrial tumor suppressor protein in renal cancer

  2010cites this paper
• Charakterisierung der Effekte verschiedener differenzierungssteigernder Substanzen auf Radioiodaufnahme, Thymidininkorporation, NIS- und Pendrin- Expression und Apoptose in der cancerogenen Schilddrüsenzelllinie FTC-238

  2010cites this paper
• Proline metabolism and microenvironmental stress.

  2010influential citation
• Gene Expression Profile Associated with Oncogenic Ras-induced Senescence, Cell Death, and Transforming Properties in Human Cells

  2010cites this paper
• Effets des ligands de PPAR[gamma] sur la voie de signalisation des oestrogènes dans les cellules cancéreuses mammaires

  2009cites this paper
• A conserved active site tyrosine residue of proline dehydrogenase helps enforce the preference for proline over hydroxyproline as the substrate.

  2009cites this paper
• Proline oxidase functions as a mitochondrial tumor suppressor in human cancers.

  2009cites this paper
• Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy

  2009influential citation
• Rosiglitazone Prevents High Glucose-Induced Vascular Endothelial Growth Factor and Collagen IV Expression in Cultured Mesangial Cells

  2009cites this paper
• Cytosolic phospholipase A 2 - (cid:1) is an early apoptotic activator in PEDF-induced endothelial cell apoptosis

  2009cites this paper
• N-acetyl cysteine mediates protection from 2-hydroxyethyl methacrylate induced apoptosis via nuclear factor kappa B-dependent and independent pathways: potential involvement of JNK.

  2009cites this paper
• Regulation and function of proline oxidase under nutrient stress

  2009cites this paper
• PPARγ ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network in colon cancer cells

  2009cites this paper
• Peroxisome Proliferator-Activated Receptor γ Pathway Targeting in Carcinogenesis: Implications for Chemoprevention

  2009cites this paper
• Thiazolidinediones as anti-cancer agents.

  2008cites this paper
• Ciglitazone Induces Caspase-Independent Apoptosis through Down-Regulation of XIAP and Survivin in Human Glioma Cells

  2008cites this paper
• Potential Benefits of Glitazones for Cancer and Vascular Disease

  2008cites this paper
• ReviewArticle PPARγ and Proline Oxidase in Cancer

  2008cites this paper
• ReviewArticle PPARγ and Apoptosis in Cancer

  2008cites this paper
• Structural basis for the inactivation of Thermus thermophilus proline dehydrogenase by N-propargylglycine.

  2008cites this paper
• Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers

  2008cites this paper
• The metabolism of proline, a stress substrate, modulates carcinogenic pathways

  2008influential citation
• Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress.

  2008cites this paper
• Structural biology of proline catabolism

  2008cites this paper
• PPARγ and Apoptosis in Cancer

  2008influential citation
• Over-expression of genes coding for proline oxidase, riboflavin kinase, cytochrome c oxidase and an MFS transporter induced by acriflavin in Trichophyton rubrum.

  2008cites this paper
• Characterization of a Helicobacter hepaticus putA Mutant Strain in Host Colonization and Oxidative Stress

  2008cites this paper
• A Novel Function for Hydroxyproline Oxidase in Apoptosis through Generation of Reactive Oxygen Species*

  2008cites this paper
• PPARγ and Proline Oxidase in Cancer

  2008influential citation