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Induction of heme-oxygenase 1 requires the p38MAPK and PI3K pathways and suppresses apoptotic cell death following hypericin-mediated photodynamic therapy

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Abstract

Photodynamic therapy (PDT) is an established anticancer modality utilizing the photogeneration of reactive oxygen species (ROS) to kill the cancer cells and hypericin is a promising photosensitizer for the treatment of bladder tumors. In this paper we characterize the signaling pathways and the mechanisms leading to the up-regulation of the antioxidant enzyme heme oxygenase (HO-1) in PDT treated cancer cells. We show that PDT engages the p38MAPK and PI3K signaling cascades for HO-1 induction. p38MAPK inhibitors or small interfering RNA (siRNA) for p38MAPK suppress HO-1 induction after PDT and complete repression is attained when p38 and PI3K antagonists are combined. Blocking these signaling pathways increases additively the propensity of the cells to undergo PDT-induced apoptosis, mirroring the effect of HO-1 silencing. Conversely, increasing HO-1 protein level by hemin prior to irradiation is cytoprotective. HO-1 stimulation by PDT is dependent on transcription and de novo protein synthesis and it is preceded by the nuclear accumulation of the Nrf2 transcription factor, which is reduced by inhibitors of p38MAPK and PI3K. Altogether these results indicate that stimulation of HO-1 expression by hypericin-PDT is a cytoprotective mechanism governed by the p38MAPK and PI3K pathways, likely through the control of the nuclear availability of the Nrf2 pool.

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Abbreviations

ActD:

actinomycin D

AREs:

antioxidant response elements

B2M:

β2-microglobulin

COX-2:

cyclooxygenase-2

ER:

endoplasmic reticulum

HO-1:

heme oxygenase 1

Hyp:

Hypericin

Nrf2:

NF-E2-related factor-2

p38MAPK :

p38 mitogen-activated protein kinase

PDT:

photodynamic therapy

PGE2 :

prostaglandin E2

PI3K:

phosphatidylinositol 3-kinase

ROS:

reactive oxygen species

ZnPPIX:

zinc protoporphyrin IX

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Acknowledgments

This work was supported by the Geconcerteerde Onderzoeksacties (GOA, from the KU.Leuven), the Interuniversitaire Attractiepolen (IAP, V/P12) of the Federal Belgian Government and by F.W.O grant G.0104.02. SK was supported by a grant from the Belgian Federal Science Policy Office.

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Authors and Affiliations

  1. Department Molecular and Cell Biology, Division of Biochemistry, Catholic University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium

    Silvia Kocanova, Esther Buytaert & Patrizia Agostinis

  2. Laboratory for Pharmaceutical Biology and Phytopharmacology, Catholic University of Leuven, B-3000, Leuven, Belgium

    Peter de Witte

  3. Laboratory of Virology and Immunology, Institute of Pathology B23 University of Liège, B-4000, Liège, Belgium

    Jean-Yves Matroule & Jacques Piette

  4. Department of Immunology, Center of Biostructure Research, The Medical University of Warsaw, Warsaw, Poland

    Jakub Golab

Authors
  1. Silvia Kocanova
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  2. Esther Buytaert
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  3. Jean-Yves Matroule
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  4. Jacques Piette
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  5. Jakub Golab
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  6. Peter de Witte
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  7. Patrizia Agostinis
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Correspondence to Patrizia Agostinis.

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Kocanova, S., Buytaert, E., Matroule, JY. et al. Induction of heme-oxygenase 1 requires the p38MAPK and PI3K pathways and suppresses apoptotic cell death following hypericin-mediated photodynamic therapy. Apoptosis 12, 731–741 (2007). https://doi.org/10.1007/s10495-006-0016-x

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  • DOI: https://doi.org/10.1007/s10495-006-0016-x

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