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GRP78-targeting Sensitizes Cancer Cells to Cytotoxic Effects of Photodynamic Therapy

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Resistance to Photodynamic Therapy in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 5))

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Abstract

Photodynamic therapy (PDT) induces cytotoxic effects against tumor cells by triggering photochemical reactions leading to the production of singlet oxygen and reactive oxygen species. Intracellular proteins have been shown to undergo oxidation-related damage in response to PDT. A number of cytoprotective mechanisms have been demonstrated to relay on mechanisms associated with removal or re-folding of these proteins or leading to the induction of unfolded protein response. The latter is regulated by GRP78, a member of the heat shock protein family that undergoes up-regulation in tumor cells in response to PDT. The most selective GRP78-targeting compound is subtilase cytotoxin (SubAB) originally isolated from Shiga toxigenic Escherichia coli strains. We observed that a fusion protein consisting of the cytotoxin catalytic A subunit (SubA) with a human epidermal growth factor (EGF) designed to selectively target EGFR-positive tumor cells increases the cytotoxic effects of PDT. Although the combination treatment activated apoptotic pathways, tumor cell death occurred in cells resistant to apoptosis and was not inhibited by inhibitors of necrotic cell death or autophagy-associated death pathways. Instead, tumor cells undergo an atypical form of cell death, which is characterized by cellular vacuolization originating from the endoplasmic reticulum.

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Acknowledgements

The work was supported by the Polish Ministry of Science grant DI2011 021141, and the European Commission 7th Framework Programme FP7-REGPOT-2012-CT2012-316254-BASTION. Figures were produced using Servier Medical Art (www.servier.com) for which the authors would like to acknowledge Servier. We would also like to thank members of our team participating in studies on the effects of EGF-SubA in combination with PDT: Joanna Barankiewicz, Antoni Domagala, Dominika Nowis, Marek Kujawa, Ewa Jankowska-Steifer, Malgorzata Wachowska, Eliza Glodkowska-Mrowka, Barbara Korsak, and Magdalena Winiarska.

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Authors and Affiliations

  1. Department of Immunology, Centre of Biostructure Research, Medical University of Warsaw, Banacha 1A F building, 02-097, Warsaw, Poland

    Malgorzata Firczuk, Magdalena Gabrysiak & Jakub Golab

  2. Institute of Physical Chemistry, Polish Academy of Sciences, 01-224, Warsaw, Poland

    Jakub Golab

Authors
  1. Malgorzata Firczuk
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  2. Magdalena Gabrysiak
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  3. Jakub Golab
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Correspondence to Jakub Golab .

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Editors and Affiliations

  1. Medical and Biological Sciences, University of Udine, Udine, Italy

    Valentina Rapozzi

  2. Prof. Ghiretti, Universita Padova Ist. Biologia Animale, Padova, Italy

    Giulio Jori

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Firczuk, M., Gabrysiak, M., Golab, J. (2015). GRP78-targeting Sensitizes Cancer Cells to Cytotoxic Effects of Photodynamic Therapy. In: Rapozzi, V., Jori, G. (eds) Resistance to Photodynamic Therapy in Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 5. Springer, Cham. https://doi.org/10.1007/978-3-319-12730-9_6

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