RADIOBIOLOGY

Le résumé fourni par la source

Glioblastoma multiforme (GBM) is the most common primary brain tumor in humans and remains a highly lethal disease.The resistance of GBM to current therapies makes the development of a novel GBM therapy crucial.Maternal embryonic leucine-zipper kinase (MELK), a member of the Snf1/AMP serine/threonine kinase family, undergoes RNA upregulation in GBM.However, the function of MELK in GBM is still poorly understood, and a targeted therapy for MELK has not yet been developed.Here, we demonstrate that MELK protein is highly expressed in malignant glioma, including GBM, and further, that MELK expression increases during the course of tumor recurrence.Radiation treatment of in vitro GBM cell cultures derived from patients substantially increased MELK expression.MELK knockdown enhanced radiation-induced apoptosis in GBM cells, whereas MELK overexpression diminished the apoptotic population in a kinase-dependent manner.Mechanistically, the treatment of GBM cells with c-JUN N-terminal kinase (JNK) inhibitor decreased MELK expression in the nucleus but not in the cytoplasm.Immunocytochemical analysis of GBM cells displayed co-localization of MELK with c-JUN, a downstream target of JNK, and c-JUN knockdown reduced MELK expression.Both JNK and MELK were up-regulated in GBM cells in comparison to normal neural cells, further supporting the significance of these molecules in GBM.Collectively, these data indicate that GBM depends on MELK and its associated pathway to maintain radioresistance.

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