NDLI: GRP78-targeting subtilase cytotoxin sensitizes cancer cells to photodynamic therapy.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Firczuk, M. Gabrysiak, M. Barankiewicz, J. Domagala, A. Nowis, D. Kujawa, M. Jankowska-Steifer, E. Wachowska, M. Glodkowska-Mrowka, E. Korsak, B. Winiarska, M. Golab, J.
Description	Country affiliation: Poland Author Affiliation: Firczuk M ( Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 1A Banacha Street, F building, 02-097 Warsaw, Poland.)
Abstract	Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER)-resident chaperone and a major regulator of the unfolded protein response (UPR). Accumulating evidence indicate that GRP78 is overexpressed in many cancer cell lines, and contributes to the invasion and metastasis in many human tumors. Besides, GRP78 upregulation is detected in response to different ER stress-inducing anticancer therapies, including photodynamic therapy (PDT). This study demonstrates that GRP78 mRNA and protein levels are elevated in response to PDT in various cancer cell lines. Stable overexpression of GRP78 confers resistance to PDT substantiating its cytoprotective role. Moreover, GRP78-targeting subtilase cytotoxin catalytic subunit fused with epidermal growth factor (EGF-SubA) sensitizes various cancer cells to Photofrin-mediated PDT. The combination treatment is cytotoxic to apoptosis-competent SW-900 lung cancer cells, as well as to Bax-deficient and apoptosis-resistant DU-145 prostate cancer cells. In these cells, PDT and EGF-SubA cytotoxin induce protein kinase R-like ER kinase and inositol-requiring enzyme 1 branches of UPR and also increase the level of C/EBP (CCAAT/enhancer-binding protein) homologous protein, an ER stress-associated apoptosis-promoting transcription factor. Although some apoptotic events such as disruption of mitochondrial membrane and caspase activation are detected after PDT, there is no phosphatidylserine plasma membrane externalization or DNA fragmentation, suggesting that in DU-145 cells the late apoptotic events are missing. Moreover, in SW-900 cells, EGF-SubA cytotoxin potentiates PDT-mediated cell death but attenuates PDT-induced apoptosis. In addition, the cell death cannot be reversed by caspase inhibitor z-VAD, confirming that apoptosis is not a major cell death mode triggered by the combination therapy. Moreover, no typical features of necrotic or autophagic cell death are recognized. Instead, an extensive cellular vacuolation of ER origin is observed. Altogether, these findings indicate that PDT and GRP78-targeting cytotoxin treatment can efficiently kill cancer cells independent on their apoptotic competence and triggers an atypical, non-apoptotic cell death.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2013.265
Journal	Cell Death and Disease
Volume Number	4
Language	English
Publisher	Nature Publishing Group
Publisher Date	2013-07-25
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Research Support, Non-u.s. Gov't Subtilisins Drug Therapy Tumor Microenvironment Pharmacology Metabolism Molecular Targeted Therapy Photochemotherapy Neoplasms Discipline Cell Biology Pathology Up-regulation Dihematoporphyrin Ether Heat-shock Proteins
Content Type	Text
Resource Type	Article

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