Chloroquine induces apoptosis in pancreatic neuroendocrine neoplasms via endoplasmic reticulum stress
Chloroquine induces apoptosis in pancreatic neuroendocrine neoplasms via endoplasmic reticulum stress
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DOI：
10.1530/erc-20-0028
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发表时间：
2020-07-01
影响因子：
3.9
通讯作者：
Uemoto, Shinji
中科院分区：
文献类型：
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作者：
Nakano, Kenzo;Masui, Toshihiko;Uemoto, Shinji
虽然胰腺神经内分泌肿瘤（PanNENs）通常是无痛的，但远处转移的患者预后不良。最近，自噬抑制剂氯喹（CQ）已被证明可以抑制PanNEN的肿瘤生长，但详细的机制尚未阐明。此外，这些结果是从低分化细胞系而不是高分化细胞系获得的，高分化细胞系是该肿瘤中最普遍的类型。为了探讨CQ对PanNENs的机制和功效，我们将CQ应用于细胞系，并评估由此产生的凋亡和内质网（ER）应激。CQ处理诱导ER应激，并且未折叠蛋白应答通过PERK-eIF 2a-ATF 4途径被激活，导致促凋亡蛋白C/EBP同源蛋白（CHOP）的表达，其反映了ER应激介导的凋亡性细胞死亡。此外，羟氯喹（HCQ）在Men 1异源性缺陷（Men 1（+）/（Delta N3-8））小鼠中有效，这是一种被认为与人类低级PanNEN相对应的小鼠PanNEN模型。HCQ给药降低了Men 1（+/Delta N3-8）小鼠的肿瘤大小。在HCQ组中，组织学分析显示增殖活性不变，但凋亡加速，伴随CHOP表达。这些结果表明，CQ/HCQ抑制自噬可用于治疗PanNEN，包括分化良好的类型。
Although pancreatic neuroendocrine neoplasms (PanNENs) are generally indolent, patients with distant metastasis have a dismal prognosis. Recently, the autophagy inhibitor chloroquine (CQ) has been shown to suppress the tumour growth of PanNENs, but the detailed mechanisms have not been elucidated. Furthermore, these results were obtained from poorly differentiated cell lines rather than well- differentiated cell lines, which is the most prevalent type in this tumour. To explore the mechanism and efficacy of CQ on PanNENs, we applied CQ to cell lines and evaluated the resulting apoptosis and endoplasmic reticulum (ER) stress. CQ treatment induced ER stress, and an unfolded protein response was activated through the PERK-eIF2a-ATF4 pathway, resulting in the expression of the pro-apoptotic protein C/EBP homologous protein (CHOP), which reflects ER-stress- mediated apoptotic cell death. Furthermore, hydroxychloroquine (HCQ) was effective in Men1 heterozygous-deficient ( Men1(+)/(Delta N3-8)) mice, a mouse PanNEN model that is considered to correspond to human low-grade PanNEN. HCQ administration decreased tumour size in Men1(+/Delta N3-8) mice. In the HCQ group, histological analyses revealed that proliferative activity was unchanged, but apoptosis was accelerated, accompanied by CHOP expression. These results suggest that autophagy inhibition by CQ/HCQ could be used for the treatment of PanNEN, including the well-differentiated type.