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Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

Oncogene volume 27, pages 1916–1929 (2008)Cite this article

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 p38MAPK 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, p38MAPK 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.

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Abbreviations

AREs:

adenylate/uridylate-rich elements

ATF:

activating transcription factor

Atg:

autophagy-related gene

CHOP:

C/EBP homologous protein

COX-2:

cyclooxygenase-2

ECM:

extracellular matrix

ER:

endoplasmic reticulum

ERAD:

ER-associated degradation

GO:

Gene Ontology

GM-CSF:

granulocyte macrophage colony-stimulating factor

HO-1:

heme oxygenase 1

Hsp:

heat shock protein

MAPK:

mitogen-activated protein kinase

MMP:

matrix metalloproteinase

Nrf2:

NF-E2-related factor 2

PDT:

photodynamic therapy

PG:

prostaglandin

PERK:

pancreatic ER kinase (PKR)-like ER kinase

ROS:

reactive oxygen species

SERCA:

sarco(endo)plasmic-reticulum Ca2+-ATPase

TCC:

transitional cell carcinoma

UPR:

unfolded protein response

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Acknowledgements

We thank Dr B Hennuy (Head of Transcriptomics—GIGA University of Liège, Belgium) for excellent handling of the microarray experiments. This work was supported by the Geconcerteerde Onderzoeksacties (GOA) and Onderzoekstoelage (OT) from the KULeuven, the Interuniversitaire Attractiepolen (IAP, Vi/P18) of the Federal Belgian Government and by FWO grant G.0104.02.

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Authors and Affiliations

  1. Department Molecular and Cell Biology, Faculty of Medicine, Catholic University of Leuven, Brabant, Belgium

    E Buytaert, S Kocanova, J R Vandenheede & P Agostinis

  2. Laboratory of Virology and Immunology, University of Liège, Liège, Belgium

    J Y Matroule, P Close & J Piette

  3. Department of Electrical Engineering, ESAT-SCD, Catholic University of Leuven, Brabant, Belgium

    S Durinck

  4. Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmacy, Catholic University of Leuven, Brabant, Belgium

    P A de Witte

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  1. E Buytaert
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  4. P Close
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Correspondence to P Agostinis.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Buytaert, E., Matroule, J., Durinck, S. et al. Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells. Oncogene 27, 1916–1929 (2008). https://doi.org/10.1038/sj.onc.1210825

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