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Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling

Oncogene volume 25, pages 5640–5647 (2006)Cite this article

Abstract

Proline oxidase (POX), often considered a ‘housekeeping enzyme’ might play an important role in apoptosis. We have shown that POX generated proline-dependent reactive oxygen species (ROS), specifically superoxide radicals, and induced apoptosis through the mitochondrial (intrinsic) pathway. 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 POX-stimulated expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), DR5 and cleavage of caspase-8. Importantly, apoptosis measured by flow cytometry was partially inhibited by Z-IETD-FMK, a specific inhibitor of caspase-8. These findings suggest that the extrinsic (death receptor) pathway also is activated by POX. Furthermore, the mechanism of this effect on the extrinsic pathway, specifically, the induction of TRAIL by POX, may be mediated by NFAT transcription factors. Additionally, POX expression also dramatically decreased phosphorylation of MEK and ERK, and the decrease was partially reversed by expression of manganese superoxide dismutase (MnSOD). Overexpression of constitutively active form of MEK, acMEK, partially blocked POX-induced apoptosis. These findings suggest the involvement of MEK/ERK signaling and further confirm the role of ROS/superoxides in POX-induced apoptosis. Combined with previously published data, we conclude that POX may induce apoptosis through both intrinsic and extrinsic pathways and is involved in nuclear factor of activated T cells (NFAT) signaling and regulation of the MEK/ERK pathway. It is suggested that, as a nutrition factor, POX may modulate apoptosis signals induced by p53 or other anti-cancer agents and enhance apoptosis in stress situations.

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Abbreviations

Ad:

adenovirus

Dox:

doxycycline

DR5:

death receptor 5

MnSOD:

manganese superoxide dismutase

MOI:

multiplicity of infection

NFAT:

nuclear factor of activated T cells

P5C:

pyrroline-5-carboxylate

PBS:

phosphate-buffered saline

PIG:

p53-induced gene

POX:

proline oxidase

ROS:

reactive oxygen species

TRAIL:

tumor necrosis factor-related apoptosis inducing ligand

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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. NO1-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.

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Authors and Affiliations

  1. Metabolism and Cancer Susceptibility Section, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA

    Y Liu, A Surazynski & J M Phang

  2. Basic Research Program, SAIC-Frederick, Inc., Frederick, MD, USA

    G L Borchert

  3. Department of Biochemistry and Molecular Biology, University of New Mexico Health Science Center, Albuquerque, NM, USA

    C-A Hu

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  1. Y Liu
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  2. G L Borchert
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Correspondence to Y Liu or J M Phang.

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Liu, Y., Borchert, G., Surazynski, A. et al. Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling. Oncogene 25, 5640–5647 (2006). https://doi.org/10.1038/sj.onc.1209564

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