Glucosylceramide Synthase Protects Glioblastoma Cells Against Autophagic and Apoptotic Death Induced by Temozolomide and Paclitaxel

Abstract

Glioblastoma is a deadly cancer with intrinsic chemoresistance. Understanding this property will aid in therapy. Glucosylceramide synthase (GCS) is associated with resistance and poor outcome; little is known about glioblastomas. In glioblastoma cells, temozolomide and paclitaxel induce ceramide increase, which in turn promotes cytotoxicity. In drug-resistant cells, both drugs are unable to accumulate ceramide, increased expression and activity of GCS is present, and its inhibitors hinder resistance. Resistant cells exhibit cross-resistance, despite differing in marker expression, and cytotoxic mechanism. These findings suggest that GCS protects glioblastoma cells against autophagic and apoptotic death, and contributes to cell survival under chemotherapy.

Keywords: :

• Autophagy
• Ceramide
• Glioblastoma
• Glucosylceramide synthase
• Temozolomide

ACKNOWLEDGMENT

This work was supported in part by grants from the Italian Ministry of University and Scientific and Technological Research PRIN and FIRST to PV and LR.

DECLARATION OF INTERESTS

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.