Langut Yael, Edinger Nufar, Flashner-Abramson Efrat, Melamed-Book Naomi, Lebendiker Mario, Levi-Kalisman Yael, Klein Shoshana, Levitzki Alexander
Department of Biological Chemistry, Unit of Cellular Signaling, Silberman Institute of Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Biological Chemistry, Unit of Bio-Imaging, Silberman Institute of Life Sciences, Safra Campus, The Hebrew University of Jerusalem, Jerusalem, Israel.
Oncotarget. 2017 Apr 11;8(15):24046-24062. doi: 10.18632/oncotarget.15733.
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.
转移性雄激素抵抗性前列腺癌的治疗仍然是一项挑战。我们描述了一种蛋白质载体，它通过靶向前列腺特异性膜抗原（PSMA）将合成的双链RNA，聚肌苷酸/聚胞苷酸（polyIC）选择性地递送至前列腺肿瘤，PSMA在前列腺癌细胞表面过表达。嵌合蛋白由与单链抗PSMA抗体相连的PKR双链RNA（dsRNA）结合域构建而成。当与polyIC复合时，该嵌合体表现出对前列腺癌细胞的选择性和高效杀伤作用。这种治疗使靶向癌细胞发生凋亡并分泌毒性细胞因子。在“旁观者效应”中，这些细胞因子杀死不一定过表达PSMA的邻近癌细胞，并激活增强杀伤作用的免疫细胞。靶向polyIC的强大作用在二维细胞培养和三维肿瘤球体上均得到了证实。
