Intercellular Transfer of Small RNAs from Astrocytes to Lung Tumor Cells Induces Resistance to Chemotherapy

Brain metastases are highly resistance to chemotherapy and have a poor prognosis for cure. Prior studies have shown that tumor cells are surrounded by activated astrocytes and exploit their cyto-protective properties for protection from apoptosis induced by chemotherapy. The mechanism by which astrocytes protect tumor cells is poorly understood. An important non-mutational mechanism of chemotherapy resistance that has received an extensive attention in the last year is regulation of gene translation mediated by small non-coding RNAs (sRNAs), in particular, microRNAs (miRNAs). Here we studied the role of astrocytic sRNAs in promoting resistance of the human lung tumor PC14 cells to apoptosis induced by chemotherapy. To this end we compared the sRNA profile of human lung tumor cells that were cultured with or without astrocytes by miRNA microarray. The results show that sRNAs are transferred from astrocytes to PC14 cells in a contact-dependent manner. This transfer is fast and reached plateau already after six hours of co-culturing. Carbenoxolone, a broad-spectrum gap junction antagonist, inhibited the sRNAs transfer indicating that the sRNAs are transferred via gap-junction. Among the sRNAs that were transferred were several sRNAs that were implicated in survival pathways. Enforced expression of these sRNA in PC14 cells increased their resistance to the chemotherapy agent Taxol. In light of these results, our research provides novel findings that can be clinically relevant to the treatment of patients with brain metastases.