Biochemical and biophysical research communications

Imatinib induces autophagy via upregulating XIAP in GIST882xa0cells.

PMID 28528977


Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms originating from the gastrointestinal tract with gain of function mutations in receptor tyrosine kinases KIT or platelet-derived growth factor receptor A (PDGFRA). The main effective treatment for GISTs is tyrosine kinase inhibitors, such as imatinib mesylate. However, GISTs respond to imatinib treatment eventually develop acquired resistance, which is a main obstacle for GISTs therapy. Therefore, it's urgent to have a better understanding of the mechanisms underlying the imatinib resistance in GISTs to develop novel therapeutic strategies. X-linked inhibitor of apoptosis (XIAP) is the most potent apoptosis inhibitor among the inhibitor of apoptosis protein (IAP) family members. Increased cellular expression of XIAP often leads to drug resistance in cancers. Here we report that XIAP is induced upon imatinb treatment in GIST882xa0cells, leading to imatinib-induced autophagy. Imatinib-induced autophagy was impaired in XIAP-knockout cells generated by CRISPR/Cas9 system demonstrated by the decreasing of LC3 lipidation. XIAP knockout sensitizes GIST882xa0cells to imatinib-induced apoptotic cell death, suggesting that XIAP protects GIST882xa0cells from imatinib-induced cell death by inducing autophagy. Thus, the resistance of the GIST882xa0cells to imatinib appears to be, in part, due to the increasing of XIAP and subsequent induction of autophagy.