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Dissecting the Entry Route of Saporin-based a-CD7 Immunotoxins in Human T-Cell Acute Lymphoblastic Leukaemia Cells
Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, I-67100, Italy
Dibit-HSR Scientific Institute and Università Vita-Salute San Raffaele, Milano, I-20132, Italy
The Simon Flavell Leukaemia Research Laboratory, Southampton General Hospital, Southampton, Hampshire SO16 6YD, UK
Istituto Nazionale di Genetica Molecolare-INGM, Milano, I-20122, Italy
* Authors to whom correspondence should be addressed.
Received: 26 November 2012; in revised form: 31 December 2012 / Accepted: 7 January 2013 / Published: 16 January 2013
Abstract: Elucidating the intracellular fate(s) of targeted toxins is of fundamental importance for their optimal use as anticancer drugs, since the biochemical targets of their enzymatic activity reside in the cell cytoplasm, as in the case of the plant ribosome inactivating proteins (RIP) saporin, ricin and of bacterial toxins. In this paper, we compared the cell surface binding and cytotoxic properties of the model RIP ricin to an immunotoxin constructed with a monoclonal antibody directed against the human T-cell marker CD7 covalently linked to saporin (CD7-SAP). Our results indicate that, despite the fact that internalization takes place via an apparently common entry route leading to the Golgi complex, surprisingly, the addition of an endoplasmic reticulum retrieval C-terminal signal (KDEL) to CD7-SAP does not potentiate its cytotoxicity. In addition, while ricin toxicity is clearly reduced by Brefeldin A under conditions where this fungal metabolite causes Golgi stack disruption, we paradoxically observed a potentiating effect by Brefeldin A on CD7-SAP cytotoxicity suggesting that this inhibitor interferes with retrograde route(s) other than the well established Trans-Golgi Network-ER retrograde route.
Keywords: endocytosis; immunotoxin; ricin; Brefeldin A; leukaemia cells
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MDPI and ACS Style
Giansanti, F.; Giordani, V.; Vago, R.; Flavell, D.J.; Flavell, S.U.; Fabbrini, M.S.; Ippoliti, R. Dissecting the Entry Route of Saporin-based a-CD7 Immunotoxins in Human T-Cell Acute Lymphoblastic Leukaemia Cells. Antibodies 2013, 2, 50-65.
Giansanti F, Giordani V, Vago R, Flavell DJ, Flavell SU, Fabbrini MS, Ippoliti R. Dissecting the Entry Route of Saporin-based a-CD7 Immunotoxins in Human T-Cell Acute Lymphoblastic Leukaemia Cells. Antibodies. 2013; 2(1):50-65.
Giansanti, Francesco; Giordani, Valeria; Vago, Riccardo; Flavell, David J.; Flavell, Sopsamorn U.; Fabbrini, Maria S.; Ippoliti, Rodolfo. 2013. "Dissecting the Entry Route of Saporin-based a-CD7 Immunotoxins in Human T-Cell Acute Lymphoblastic Leukaemia Cells." Antibodies 2, no. 1: 50-65.