Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Oncogene volume 27, pages 6729–6737 (2008)Cite this article

Abstract

Proline oxidase (POX), a flavoenzyme localized at the inner mitochondrial membrane, catalyzes the first step of proline degradation by converting proline to pyrroline-5-carboxylate (P5C). POX is markedly elevated during p53-induced apoptosis and generates proline-dependent reactive oxygen species (ROS), specifically superoxide radicals, to induce apoptosis through both mitochondrial and death receptor pathways. These previous studies also showed suppression of the mitogen-activated protein kinase pathway leading us to broaden our exploration of proliferative signaling. In our current report, we used DLD-1 colorectal cancer cells stably transfected with the POX gene under the control of a tetracycline-inducible promoter and found that three pathways which cross talk with each other were downregulated by POX: the cyclooxygenase-2 (COX-2) pathway, the epidermal growth factor receptor (EGFR) pathway and the Wnt/β-catenin pathway. First, POX markedly reduced COX-2 expression, suppressed the production of prostaglandin E2 (PGE2) and importantly, the growth inhibition by POX was partially reversed by treatment with PGE2. Phosphorylation of EGFR was decreased with POX expression and the addition of EGF partially reversed the POX-dependent downregulation of COX-2. Wnt/β-catenin signaling was decreased by POX in that phosphorylation of glycogen synthase kinase-3β (GSK-3β) was decreased on the one hand and phosphorylation of β-catenin was increased on the other. There changes led to decreased accumulation of β-catenin and decreased β-catenin/TCF/LEF-mediated transcription. Our newly described POX-mediated suppression of proliferative signaling together with the previously reported induction of apoptosis suggested that POX could function as a tumor suppressor. Indeed, in human colorectal tissue samples, immunohistochemically-monitored POX was dramatically decreased in tumors compared with normal counterparts. Thus, POX metabolism of substrate proline affects multiple signaling pathways, modulating both apoptosis and tumor growth, and could be an attractive target to metabolically control the cancer phenotypes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Abbreviations

APC:

adenomatous polyposis coli

COX-2:

cyclooxygenase-2

DOX:

doxycycline

EGFR:

epidermal growth factor receptor

MnSOD:

manganese superoxide dismutase

P5C:

pyrroline-5-carboxylate

PGE2:

prostaglandin E2

POX:

proline oxidase

ROS:

reactive oxygen species

TCA:

tricarboxylic acid

References

  • Albini A, Sporn MB . (2007). The tumor microenvironment as a target for chemoprevention. Nat Rev Cancer 7: 139–147.

    Article  CAS  PubMed  Google Scholar 

  • Araki Y, Okamura S, Hussain SP, Nagashima M, He P, Shiseki M et al. (2003). Regulation of cyclooxygenase-2 expression by the Wnt and ras pathways. Cancer Res 63: 728–734.

    CAS  PubMed  Google Scholar 

  • Bensaad K, Vousden KH . (2007). p53: new roles in metabolism. Trends Cell Biol 17: 286–291.

    Article  CAS  PubMed  Google Scholar 

  • Buchanan FG, Wang D, Bargiacchi F, DuBois RN . (2003). Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 278: 35451–35457.

    Article  CAS  PubMed  Google Scholar 

  • Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS . (2005). Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 310: 1504–1510.

    Article  CAS  PubMed  Google Scholar 

  • Chen JJ, Huang WC, Chen CC . (2005). Transcriptional regulation of cyclooxygenase-2 in response to proteasome inhibitors involves reactive oxygen species-mediated signaling pathway and recruitment of CCAAT/enhancer-binding protein delta and CREB-binding protein. Mol Biol Cell 16: 5579–5591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dannenberg AJ, Lippman SM, Mann JR, Subbaramaiah K, DuBois RN . (2005). Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 23: 254–266.

    Article  CAS  PubMed  Google Scholar 

  • Dixon DA . (2004). Dysregulated post-transcriptional control of COX-2 gene expression in cancer. Curr Pharm Des 10: 635–646.

    Article  CAS  PubMed  Google Scholar 

  • Dixon DA, Kaplan CD, McIntyre TM, Zimmerman GA, Prescott SM . (2000). Post-transcriptional control of cyclooxygenase-2 gene expression. The role of the 3′-untranslated region. J Biol Chem 275: 11750–11757.

    Article  CAS  PubMed  Google Scholar 

  • Donald SP, Sun XY, Hu CA, Yu J, Mei JM, Valle D et al. (2001). Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species. Cancer Res 61: 1810–1815.

    CAS  PubMed  Google Scholar 

  • Gupta RA, Dubois RN . (2001). Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1: 11–21.

    Article  CAS  PubMed  Google Scholar 

  • Hagedorn CH, Phang JM . (1986). Catalytic transfer of hydride ions from NADPH to oxygen by the interconversions of proline and delta 1-pyrroline-5-carboxylate. Arch Biochem Biophys 248: 166–174.

    Article  CAS  PubMed  Google Scholar 

  • Huang B, Starostik P, Kuhl J, Tonn JC, Roggendorf W . (2002). Loss of heterozygosity on chromosome 22 in human ependymomas. Acta Neuropathol (Berl) 103: 415–420.

    Article  CAS  Google Scholar 

  • Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al. (2005). Cancer statistics, 2005. CA Cancer J Clin 55: 10–30.

    Article  PubMed  Google Scholar 

  • Kawamori T, Rao CV, Seibert K, Reddy BS . (1998). Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res 58: 409–412.

    CAS  PubMed  Google Scholar 

  • Kim J, Adam RM, Freeman MR . (2005). Trafficking of nuclear heparin-binding epidermal growth factor-like growth factor into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress. Cancer Res 65: 8242–8249.

    Article  CAS  PubMed  Google Scholar 

  • Kinzler KW, Vogelstein B . (1996). Lessons from hereditary colorectal cancer. Cell 87: 159–170.

    Article  CAS  PubMed  Google Scholar 

  • Korswagen HC . (2006). Regulation of the Wnt/beta-catenin pathway by redox signaling. Dev Cell 10: 687–688.

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Lazenby AJ, Siegal GP . (2006a). Signal transduction cross talk during colorectal tumorigenesis. Adv Anat Pathol 13: 270–274.

    Article  PubMed  Google Scholar 

  • Liu Y, Borchert GL, Donald SP, Surazynski A, Hu CA, Weydert CJ et al. (2005). MnSOD inhibits proline oxidase-induced apoptosis in colorectal cancer cells. Carcinogenesis 26: 1335–1342.

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Borchert GL, Phang JM . (2004). Polyoma enhancer activator 3, an ets transcription factor, mediates the induction of cyclooxygenase-2 by nitric oxide in colorectal cancer cells. J Biol Chem 279: 18694–18700.

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Borchert GL, Surazynski A, Hu CA, Phang JM . (2006b). Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling. Oncogene 25: 5640–5647.

    Article  CAS  PubMed  Google Scholar 

  • Maxwell SA, Rivera A . (2003). Proline oxidase induces apoptosis in tumor cells, and its expression is frequently absent or reduced in renal carcinomas. J Biol Chem 278: 9784–9789.

    Article  CAS  PubMed  Google Scholar 

  • McDonald-McGinn DM, Reilly A, Wallgren-Pettersson C, Hoyme HE, Yang SP, Adam MP et al. (2006). Malignancy in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Am J Med Genet A 140: 906–909.

    Article  PubMed  Google Scholar 

  • Merida I, Avila-Flores A . (2006). Tumor metabolism: new opportunities for cancer therapy. Clin Transl Oncol 8: 711–716.

    Article  CAS  PubMed  Google Scholar 

  • Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E et al. (1996). Suppression of intestinal polyposis in APC delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87: 803–809.

    Article  CAS  PubMed  Google Scholar 

  • Pandhare J, Cooper SK, Phang JM . (2006). Proline oxidase, a proapoptotic gene, is induced by troglitazone: evidence for both peroxisome proliferator-activated receptor gamma-dependent and -independent mechanisms. J Biol Chem 281: 2044–2052.

    Article  CAS  PubMed  Google Scholar 

  • Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B . (1997). A model for p53-induced apoptosis. Nature 389: 300–305.

    Article  CAS  PubMed  Google Scholar 

  • Prescott SM, Fitzpatrick FA . (2000). Cyclooxygenase-2 and carcinogenesis. Biochim Biophys Acta 1470: M69–M78.

    CAS  PubMed  Google Scholar 

  • Rivera A, Maxwell SA . (2005). The p53-induced gene-6 (proline oxidase) mediates apoptosis through a calcineurin-dependent pathway. J Biol Chem 280: 29346–29354.

    Article  CAS  PubMed  Google Scholar 

  • Sevenet N, Lellouch-Tubiana A, Schofield D, Hoang-Xuan K, Gessler M, Birnbaum D et al. (1999). Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations. Hum Mol Genet 8: 2359–2368.

    Article  CAS  PubMed  Google Scholar 

  • Shao J, Evers BM, Sheng H . (2004). Prostaglandin E2 synergistically enhances receptor tyrosine kinase-dependent signaling system in colon cancer cells. J Biol Chem 279: 14287–14293.

    Article  CAS  PubMed  Google Scholar 

  • Shao J, Jung C, Liu C, Sheng H . (2005). Prostaglandin E2 Stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer. J Biol Chem 280: 26565–26572.

    Article  CAS  PubMed  Google Scholar 

  • Surazynski A, Donald S, Cooper S, Whiteside M, Salnikow K, Liu Y et al. (2008). Extracellular Matrix and HIF-1 signaling: the role of prolidase. Int J Cancer 122: 1435–1440.

    Article  CAS  PubMed  Google Scholar 

  • Williams CS, Smalley W, DuBois RN . (1997). Aspirin use and potential mechanisms for colorectal cancer prevention. J Clin Invest 100: 1325–1329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ et al. (2007). The genomic landscapes of human breast and colorectal cancers. Science 318: 1108–1113.

    Article  CAS  PubMed  Google Scholar 

  • Worthley DL, Whitehall VL, Spring KJ, Leggett BA . (2007). Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol 13: 3784–3791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yeh GC, Phang JM . (1988). Stimulation of phosphoribosyl pyrophosphate and purine nucleotide production by pyrroline 5-carboxylate in human erythrocytes. J Biol Chem 263: 13083–13089.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project also has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health under Contract No. N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Author information

Authors and Affiliations

  1. Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD, USA

    Y Liu & G L Borchert

  2. Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA

    A Surazynski & J M Phang

Authors
  1. Y Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G L Borchert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Surazynski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J M Phang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Y., Borchert, G., Surazynski, A. et al. Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers. Oncogene 27, 6729–6737 (2008). https://doi.org/10.1038/onc.2008.322

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.322

Keywords

This article is cited by

Search

Advanced search

Quick links