Targeted inhibition of p38alpha MAPK suppresses tumor-associated endothelial cell migration in response to hypericin-based photodynamic therapy.
Photodynamic therapy (PDT) is an established anticancer modality and hypericin is a promising photosensitizer for the treatment of bladder tumors. We show that exposure of bladder cancer cells to hypericin PDT leads to a rapid rise in the cytosolic calcium concentration which is followed by the generation of arachidonic acid by phospholipase A2 (PLA2). PLA2 inhibition significantly protects cells from the PDT-induced intrinsic apoptosis and attenuates the activation of p38 MAPK, a survival signal mediating the up-regulation of cyclooxygenase-2 that converts arachidonic acid into prostanoids. Importantly, inhibition of p38alpha MAPK blocks the release of vascular endothelial growth factor and suppresses tumor-promoted endothelial cell migration, a key step in angiogenesis. Hence, targeted inhibition of p38alpha MAPK could be therapeutically beneficial to PDT, since it would prevent COX-2 expression, the inducible release of growth and angiogenic factors by the cancer cells, and cause an increase in the levels of free arachidonic acid, which promotes apoptosis.
Hendrickx
Nico
N
Department Molecular and Cell Biology, Catholic University of Leuven, Leuven, Belgium.
Dewaele
Michael
M
Buytaert
Esther
E
Marsboom
Glenn
G
Janssens
Stefan
S
Van Boven
Maurits
M
Vandenheede
Jackie R
JR
de Witte
Peter
P
Agostinis
Patrizia
P
D000873:Anthracenes; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D016503:Drug Delivery Systems / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006367:HeLa Cells; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D010569:Perylene / Q000031:analogs & derivatives; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects
D000873:Anthracenes; D004791:Enzyme Inhibitors; D017319:Photosensitizing Agents; D010569:Perylene; C004965:hypericin; D011493:Protein Kinase C; D048308:Mitogen-Activated Protein Kinase 14