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Apoptosis

, Volume 12, Issue 4, pp 731–741 | Cite as

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

  • Silvia Kocanova
  • Esther Buytaert
  • Jean-Yves Matroule
  • Jacques Piette
  • Jakub Golab
  • Peter de Witte
  • Patrizia AgostinisEmail author
Article

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.

Keywords

HO-1 Apoptosis PDT Hypericin Reactive oxygen species Cancer therapy PI3K p38MAPK Nrf2 

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

Notes

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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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Silvia Kocanova
    • 1
  • Esther Buytaert
    • 1
  • Jean-Yves Matroule
    • 3
  • Jacques Piette
    • 3
  • Jakub Golab
    • 4
  • Peter de Witte
    • 2
  • Patrizia Agostinis
    • 1
    Email author
  1. 1.Department Molecular and Cell BiologyDivision of Biochemistry, Catholic University of LeuvenLeuvenBelgium
  2. 2.Laboratory for Pharmaceutical Biology and PhytopharmacologyCatholic University of LeuvenLeuvenBelgium
  3. 3.Laboratory of Virology and ImmunologyInstitute of Pathology B23 University of LiègeLiègeBelgium
  4. 4.Department of ImmunologyCenter of Biostructure Research, The Medical University of WarsawWarsawPoland

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