The molecular basis of prostate cancer cell escape from protoporphyrin IX-based photodynamic therapy

Abstract

Abstract Introduction Photodynamic therapy (PDT) uses the combination of a photosensitizing drug and light to cause selective damage to solid tumors. For early or localized disease, PDT can be a curative therapy with many advantages over available alternatives. For more advanced or disseminated disease, curative therapy is usually not possible with current technologies of light application, nevertheless it can improve quality of life and lengthen survival. More recently, there has been increasing evidence that PDT can also induce systemic anti-tumor immunity, indicating that PDT can become a rational therapeutic option, even if not all tumor cells are primarily eliminated by PDT. One prerequisite to minimize tumor relapse in these settings is to elucidate how tumor cells can cope with the PDT-induced damage. Material and methods Here we have characterized the rescue response of human PC-3 prostate cancer cells exposed in vitro to sublethal PDT after 5-aminolevulinic acid-induced protoporphyrin IX sensitization at the transcriptome level using Affymetrix HG U133 Plus 2.0 oligonucleotide microarrays. Cells were irradiated with laser light at a wavelength of 635 nm adjusted to an irradiance of 100 mW/cm 2 with irradiations of 1.5 and 3 J/cm 2 . Results The early response was characterized by the up-regulation of early response genes like FOS , JUN , EGR1 , ATF3 , DUSP , heat shock protein genes as well as histone genes, therefore resembling the early response of tumor cells to high dose PDT but without signs of irreversible cell damage. Twenty-four hours after PDT the cells still express high level of early response genes but 235 additional probe sets/genes were now significantly up-regulated (≥3 x ) that were not up-regulated 4 h after PDT. The most prominently up-regulated genes belong to gene families encoding the aldo-keto reductases, fibroblast growth factors, and HSP40-related proteins. In terms of a possible anti-tumor immune response it is noteworthy that also a multitude of chemokine and interleukin genes were up-regulated by the tumor cells upon PDT. Most of them are involved in granulocyte attraction and activation and some are also important for angiogenesis. Conclusion In conclusion, the global molecular characterization of the rescue response to PDT of tumor cells indicates that PDT rather favors an anti-tumor immune response than tumor immune escape reactions. Therefore, combining PDT and immunotherapy seem to be an attractive direction for the establishment of novel multimodal tumor therapies.