Glioblastoma multiforme (GBM) is among the deadliest
cancers, owing in part to complex inter- and intra-
tumor heterogeneity and the presence of a population of stem-like cells called brain tumour stem cells (BTSCs/BTICs). These cancer stem cells survive treatment and confer resistance to the current
therapies - namely, radiation and the chemotherapeutic,
temozolomide (TMZ). TMZ induces cell death by alkylating
DNA, and BTSCs resist this mechanism via a robust DNA damage response. Hence, recent studies aimed to sensitize BTSCs to TMZ using combination
therapy, such as inhibition of DNA repair machinery. We have previously demonstrated in established GBM cell lines that eukaryotic
initiation factor 5B (
eIF5B) promotes the translation of pro-survival and
anti-apoptotic proteins. Consequently, silencing
eIF5B sensitizes these cells to TRAIL-induced apoptosis. However, established cell lines do not always recapitulate the features of human
glioma. Therefore, we investigated this mechanism in patient-derived BTSCs. We show that silencing
eIF5B leads to increased TMZ sensitivity in two BTSC lines: BT25 and BT48. Depletion of
eIF5B decreases the levels of
anti-apoptotic proteins in BT48 and sensitizes these cells to TMZ-induced activation of
caspase-3, cleavage of PARP, and apoptosis. We suggest that
eIF5B represents a rational target to sensitize GBM
tumors to the current standard-of-care.