Xie Qingqing, Lin Qi, Li Dezhi, Chen Jianming
School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China.
Key Laboratory of Marine Genetic Resources, Fujian Collaborative Innovation Center for Exploitation and Utilization of Marine Biological Resources, Third Institute of Oceanography, Xiamen, Fujian 361005, China.
Biochem Biophys Res Commun. 2017 Jul 8;488(4):584-589. doi: 10.1016/j.bbrc.2017.05.096. Epub 2017 May 18.
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 GIST882 cells, 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 GIST882 cells to imatinib-induced apoptotic cell death, suggesting that XIAP protects GIST882 cells from imatinib-induced cell death by inducing autophagy. Thus, the resistance of the GIST882 cells to imatinib appears to be, in part, due to the increasing of XIAP and subsequent induction of autophagy.
胃肠道间质瘤（GISTs）是最常见的起源于胃肠道的间充质肿瘤，其受体酪氨酸激酶KIT或血小板衍生生长因子受体A（PDGFRA）存在功能获得性突变。GISTs的主要有效治疗方法是酪氨酸激酶抑制剂，如甲磺酸伊马替尼。然而，对伊马替尼治疗有反应的GISTs最终会产生获得性耐药，这是GISTs治疗的主要障碍。因此，迫切需要更好地了解GISTs中伊马替尼耐药的机制，以开发新的治疗策略。X连锁凋亡抑制蛋白（XIAP）是凋亡抑制蛋白（IAP）家族成员中最有效的凋亡抑制剂。XIAP细胞表达增加通常会导致癌症耐药。在此我们报告，在GIST882细胞中，伊马替尼治疗可诱导XIAP表达，导致伊马替尼诱导的自噬。通过CRISPR/Cas9系统产生的XIAP基因敲除细胞中，伊马替尼诱导的自噬受损，这可通过LC3脂化减少得以证明。XIAP基因敲除使GIST882细胞对伊马替尼诱导的凋亡性细胞死亡敏感，这表明XIAP通过诱导自噬保护GIST882细胞免受伊马替尼诱导的细胞死亡。因此，GIST882细胞对伊马替尼的耐药性似乎部分归因于XIAP的增加及随后自噬的诱导。
