Glioblastoma multiforme (GBM) is the most frequent and deadly brain tumor. Many
sphingolipids are crucial players in the regulation of glioma cell growth as well as in the response
to different chemotherapeutic drugs. In particular, ceramide (Cer) is a tumor suppressor lipid, able
to induce antiproliferative and apoptotic responses in different types of tumors including GBM,
most of which overexpress the epidermal growth factor receptor variant III (EGFRvIII). In this
paper, we investigated whether Cer metabolism is altered in the U87MG human glioma cell line
overexpressing EGFRvIII (EGFR+ cells) to elucidate their possible interplay in the mechanisms
regulating GBM survival properties and the response to the alkylating agent temozolomide (TMZ).
Notably, we demonstrated that a low dose of TMZ significantly increases Cer levels in U87MG cells
but slightly in EGFR+ cells (sensitive and resistant to TMZ, respectively). Moreover, the inhibition
of the synthesis of complex sphingolipids made EGFR+ cells sensitive to TMZ, thus involving Cer
accumulation/removal in TMZ resistance of GBM cells. This suggests that the enhanced resistance of
EGFR+ cells to TMZ is dependent on Cer metabolism. Altogether, our results indicate that EGFRvIII
expression confers a TMZ-resistance phenotype to U87MG glioma cells by counteracting Cer increase
