Exosomal p38 Mitogen-activated Protein Kinase Promotes Tumour Repopulation in TP53-mutated Bile Duct Cancer Cells

Background/Aim: Tumour repopulation is a major obstacle for successful cancer treatment. This study investigated whether anticancer agents contribute to tumour repopulation in TP53-mutated bile duct cancer cells. Materials and Methods: TP53-mutated HuCCT1 and HuH28 cells were exposed to anticancer agents, and recipient cells were exposed to their conditioned media or exosomes. The effect of inhibitors and siRNA-mediated gene silencing of p38 mitogen-activated protein kinase (MAPK) and of TP53 was analyzed by cell proliferation assays and western blotting. Results: Conditioned media from genotoxic agent-treated cells promoted proliferation of recipient cells (p<0.05), and this effect was abrogated by exosome inhibitors. Exosomes from gemcitabine- or cisplatintreated cells increased cell proliferation by 1.6- to 2.2-fold (p<0.05) through p38 MAPK signalling. These effects of exosomes were inhibited by inhibition/silencing of p38 MAPK but not by TP53 silencing. Conclusion: Exosomal p38 MAPK plays a pivotal role in tumour repopulation in a TP53independent manner.