Intercellular transfer of small RNAs from astrocytes to lung tumor cells induces resistance to chemotherapy
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Assaf Menachem1, Victoria Makovski1, Or Bodner1, Metsada Pasmanik-Chor2, Reuven Stein1, Noam Shomron3, Yoel Kloog1
1Department of Neurobiology, Tel Aviv University, 69978 Tel Aviv, Israel
2Bioinformatics Unit, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel
3Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel
Assaf Menachem, e-mail: [email protected]
Yoel Kloog, e-mail: [email protected]
Keywords: astrocytes, small RNA, lung tumor, intercellular transfer, chemotherapy
Received: October 04, 2015 Accepted: January 23, 2016 Published: February 09, 2016
Brain metastases are resistant to chemotherapy and carry a poor prognosis. Studies have shown that tumor cells are surrounded by activated astrocytes, whose cytoprotective properties they exploit for protection from chemotherapy-induced apoptosis. The mechanism of such astrocytic protection is poorly understood. A non-mutational mechanism of resistance to chemotherapy that is receiving increased attention is the regulation of gene translation mediated by small noncoding RNAs (sRNAs), and particularly microRNAs (miRNAs). With the aim of examining the role of astrocytic sRNAs in promoting resistance of human lung tumor PC14 cells to chemotherapy-induced apoptosis, here we used a miRNA microarray to compare sRNA profiles of human lung tumor cells cultured with and without astrocytes. We found that sRNAs are transferred from astrocytes to PC14 cells in a contact-dependent manner. Transfer was rapid, reaching a plateau after only 6 hours in culture. The sRNA transfer was inhibited by the broad-spectrum gap-junction antagonist carbenoxolone, indicating that transfer occurs via gap junctions. Among the transferred sRNAs were several that are implicated in survival pathways. Enforced expression of these sRNAs in PC14 cells increased their resistance to the chemotherapeutic agent paclitaxel. These novel findings might be of clinical relevance for the treatment of patients with brain metastases.
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