Induction of heme-oxygenase 1 requires the p38MAPK and PI3K pathways and suppresses apoptotic cell death following hypericin-mediated photodynamic therapy.
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 p38(MAPK) and PI3K signaling cascades for HO-1 induction. p38(MAPK) inhibitors or small interfering RNA (siRNA) for p38(MAPK) 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 p38(MAPK) and PI3K. Altogether these results indicate that stimulation of HO-1 expression by hypericin-PDT is a cytoprotective mechanism governed by the p38(MAPK) and PI3K pathways, likely through the control of the nuclear availability of the Nrf2 pool.
Kocanova
Silvia
S
Department Molecular and Cell Biology, Division of Biochemistry, Catholic University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Buytaert
Esther
E
Matroule
Jean-Yves
JY
Piette
Jacques
J
Golab
Jakub
J
de Witte
Peter
P
Agostinis
Patrizia
P
D000873:Anthracenes; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D010569:Perylene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010778:Photochemotherapy; D034741:RNA, Small Interfering / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000873:Anthracenes; D004791:Enzyme Inhibitors; D051547:Heme Oxygenase-1; D051267:NF-E2-Related Factor 2; D010569:Perylene; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D048051:p38 Mitogen-Activated Protein Kinases; C495635:NFE2L2 protein, human; C004965:hypericin