R-CRT rules Bortezomib susceptibility of Human Glioma cells between autophagy and ER stress

HALLAK ME; BONNET, LV; GALIANO MR; FLORES MARTIN J

Buenos Aires

Workshop; Buenos Aires Research Conferences on Autophagy. Molecular Mechanism in Biology and Diseases; 2017

In human glioma cells we determined that susceptibility to Bortezomib treatment (BT) correlates with variable expression and subcellular localization of arginylated calreticulin (R-CRT). BT-resistant MO59K cells had a small variation of R-CRT, which is associated with increased stress granules (SGs) formation and sharp ER stress. BT-susceptible HOG cells showed increased levels of R-CRT, after strong ER stress induced by Bortezomib. The BT cytotoxic effect showed by HOG became null when Tannic Acid (TA, Ate1 inhibitor) was added. HOG co-treated with BT and TA showed an increase of SGs formation in agreement with their enhanced BT resistance, whereas reduced SGs were observed in co-treated MO59K. We further evaluate autophagy activation during BT in both cell types, considering its role in degradation of SGs. HOG showed a strong activation of autophagy, even in control condition, whereas MO59K did not show this effect. Hence, the increased BT susceptibility of HOG is associated with active autophagy and robust induction of ER stress, which promotes arginylation of CRT and R-CRT exposure at plasma membrane. By contrast, MO59K develops a controlled induction of both autophagy and ER stress, maintaining reduced levels of R-CRT that mainly associates with SGs, as a hallmark of BT resistance.