ER stress promotion by Bortezomib treatment is associated with R-CRT pro-apoptotic action in human glioma cells

LAURA V. BONNET; ANDREA COMBA; VICTOR E. GOITEA; MAURICIO R. GALIANO; MARTA E. HALLAK

Buenos Aires

Congreso; Congreso FALAN 2016; 2016

Federacion de Sociedades de Neurociencia de Latinoamerica y el Caribe FALAN

Among different human glioma cells, we determined a differential susceptibility to Bortezomib treatment (BT) that correlates with variable expression levels and subcellular localization of arginylated calreticulin (R-CRT). Those cells (MO59K) that are resistant to BT showed a small variation of R-CRT, which appears confined to increased stress granules (SGs) formation. Whereas those cells (HOG) that are susceptible to BT showed intracellular increased levels and plasma membrane enrichment of R-CRT, where it participates in a caspase 3 dependent pro-apoptotic signaling. In order to establish which mechanisms promote the differential expression of R-CRT in glioma cells after BT, we evaluated if Bortezomib elicited activation of ER stress and/or intracellular Calcium mobilization. Fluorescence activation of FLUO-3 evidences a robust mobilization of intracellular calcium when HOG cells are exposed to BT. Whereas MO59K cells that are resistant to BT promote a sparse mobilization of calcium during different times of BT. In addition, the analysis by Western blot of different ER stress markers showed that in HOG cells BT mediates a stronger activation of ER stress than that observed in MO59K. These events are directly related with the variations of R-CRT observed in each cell type after BT, suggesting a mechanism of efficient chemotherapy encompassing: ER stress, increased arginylation of CRT, its re-localization to cell membrane and proper apoptosis induction.