1. ¹Department Molecular and Cell Biology, Faculty of Medicine, Catholic University of Leuven, Brabant, Belgium
2. ²Laboratory of Virology and Immunology, University of Liège, Liège, Belgium
3. ³Department of Electrical Engineering, ESAT-SCD, Catholic University of Leuven, Brabant, Belgium
4. ⁴Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmacy, Catholic University of Leuven, Brabant, Belgium

Correspondence: Dr P Agostinis, Department Molecular and Cell Biology, KULeuven, Herestraat 49, Campus Gasthuisberg, Leuven, Brabant 3000, Belgium. E-mail: patrizia.agostinis@med.kuleuven.be

Received 29 January 2007; Revised 19 July 2007; Accepted 5 September 2007; Published online 22 October 2007.

Abstract

Photodynamic therapy (PDT) is an anticancer approach utilizing a light-absorbing molecule and visible light irradiation to generate, in the presence of O₂, cytotoxic reactive oxygen species, which cause tumor ablation. Given that the photosensitizer hypericin is under consideration for PDT treatment of bladder cancer we used oligonucleotide microarrays in the T24 bladder cancer cell line to identify differentially expressed genes with therapeutic potential. This study reveals that the expression of several genes involved in various metabolic processes, stress-induced cell death, autophagy, proliferation, inflammation and carcinogenesis is strongly affected by PDT and pinpoints the coordinated induction of a cluster of genes involved in the unfolded protein response pathway after endoplasmic reticulum stress and in antioxidant response. Analysis of PDT-treated cells after p38^MAPK inhibition or silencing unraveled that the induction of an important subset of differentially expressed genes regulating growth and invasion, as well as adaptive mechanisms against oxidative stress, is governed by this stress-activated kinase. Moreover, p38^MAPK inhibition blocked autonomous regrowth and migration of cancer cells escaping PDT-induced cell death. This analysis identifies new molecular effectors of the cancer cell response to PDT opening attractive avenues to improve the therapeutic efficacy of hypericin-based PDT of bladder cancer.