Glucosidase II beta subunit (GluIIβ) plays a role in autophagy and apoptosis regulation in lung carcinoma cells in a p53-dependent manner

Abstract

Our data indicate that GluIIβ inhibition results in autophagy and apoptosis in lung carcinoma-derived cells, supporting the hypothesis that this enzyme may play a role in blocking these two tumor suppressive processes. Since blocking autophagy by lysosomal inhibitors enhanced the apoptosis-inducing effect of bromoconduritol, independent of p53 status, their combined use may hold promise for the treatment of cancer, particularly lung cancer.

Knockout of glucosidase II beta subunit inhibits growth and metastatic potential of lung cancer cells by inhibiting receptor tyrosine kinase activities

“…mTOR 33 , thus RTKs inhibition can have a direct impact over autophagy regulation. Accordingly, suppression of GluIIβ activity either by a selective inhibitor or siRNA technology has been repeatedly reported to cause an induction of autophagy 4,5 , which may additionally be support by our finding that knock-out of GluIIβ down-regulated multiple RTK signaling activities leading to autophagy. Our previous study demonstrated that suppression of GluIIβ not only induced autophagy but also induced apoptosis, and the inhibition of autophagy could enhance the apoptosis inducing effect of GluIIβ suppression.…”

“…We previously reported detecting increased expression of GlluIIß in a high proportion of lung carcinoma tissues 3 , and suppression of GlluIIß triggered cells to undergo autophagy and/or apoptosis 4–6 . In this study we have demonstrated that knockout of GlluIIß significantly decreased viability, migration, anchorage-independent growth and RTKs signaling activities of lung cancer cells.…”

“…The phosphorylation level of EGFR in our study was lower than the detection limit of the RTK Phosphorylation Antibody Array, thus EGFR phosphorylation was not one of the 51 suppressed RTKs identified in GluIIβ knockout cells. Nevertheless, we have previously demonstrated that suppression of GluIIβ activity decreased EGFR/RTK signaling activity by a flow cytometry-based method 4 . Thus, we hypothesizes that GluIIβ knockout cells may already possess lower levels of EGFR together with other RTKs activities and thus any additional blocking of EGFR by gefitinib does not significantly further impact their growth.…”

“…Although GluIIβ suppression may represent a better approach by blocking multiple RTKs signaling pathways, without inhibition of autophagy this approach may also lead to autophagy and acquired resistance. Therefore, treatment with a GluIIβ inhibitor combined with the inhibition of autophagy represents a very effective approach to induce apoptotic cell death of cancer cells 4 .…”

“…The balance between glucosidase II and UGT1 activity is fundamental to maintain the quality of the protein folding process within the ER. GluIIβ was reported to be frequently overexpressed in non-small cell lung carcinoma (NSCLC) 3 and suppression of its expression and/or activity has been reported to dose dependently inactivated EGFR/RTK and PI3K/AKT signaling pathways 4 , causing autophagy 4,5 and apoptosis 4,6 . The observations that GluIIβ suppression caused a decrease of EGFR/RTK and PI3K/AKT signaling activities lead to the hypothesis that tumor cells may rely on the activation of GluIIβ expression to help activate RTKs activities and advance their progression.…”