Oncotarget

Priority Research Papers:

PSMA-homing dsRNA chimeric protein vector kills prostate cancer cells and activates anti-tumor bystander responses

Yael Langut, Nufar Edinger, Efrat Flashner-Abramson, Naomi Melamed-Book, Mario Lebendiker, Yael Levi-Kalisman, Shoshana Klein and Alexander Levitzki _

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Oncotarget. 2017; 8:24046-24062. https://doi.org/10.18632/oncotarget.15733

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Abstract

Yael Langut1, Nufar Edinger1, Efrat Flashner-Abramson1, Naomi Melamed-Book2, Mario Lebendiker3, Yael Levi-Kalisman4, Shoshana Klein1 and Alexander Levitzki1

1 Department of Biological Chemistry, Unit of Cellular Signaling, Silberman Institute of Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem, Israel

2 Department of Biological Chemistry, Unit of Bio-Imaging, Silberman Institute of Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem, Israel

3 The Protein Purification Facility, Wolfson Center for Applied Structural Biology, Silberman Institute of Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem, Israel

4 The Center for Nanoscience and Nanotechnology, Silberman Institute for Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem, Israel

Correspondence to:

Alexander Levitzki, email:

Keywords: PSMA, polyIC, dsRNA binding domain, ScFvJ591

Received: October 07, 2016 Accepted: February 11, 2017 Published: February 25, 2017

Abstract

The treatment of metastatic androgen-resistant prostate cancer remains a challenge. We describe a protein vector that selectively delivers synthetic dsRNA, polyinosinic/polycytidylic acid (polyIC), to prostate tumors by targeting prostate specific membrane antigen (PSMA), which is overexpressed on the surface of prostate cancer cells.

The chimeric protein is built from the double stranded RNA (dsRNA) binding domain of PKR tethered to a single chain anti-PSMA antibody. When complexed with polyIC, the chimera demonstrates selective and efficient killing of prostate cancer cells. The treatment causes the targeted cancer cells to undergo apoptosis and to secrete toxic cytokines. In a “bystander effect”, these cytokines kill neighboring cancer cells that do not necessarily overexpress PSMA, and activate immune cells that enhance the killing effect. The strong effects of the targeted polyIC are demonstrated on both 2D cell cultures and 3D tumor spheroids.


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