Inhibition of lysosomal acid β-glucosidase induces cell apoptosis via impairing mitochondrial clearance in pancreatic cancer.
Inhibition of lysosomal acid β-glucosidase induces cell apoptosis via impairing mitochondrial clearance in pancreatic cancer.
复制标题
在胰腺癌中，溶酶体酸性 β-葡萄糖苷酶的抑制通过损害线粒体清除来诱导细胞凋亡。
DOI：
10.1093/carcin/bgac060
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Ikegami T.
中科院分区：
文献类型：
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作者：
Yanagaki M;Shirai Y;Shimada Y;Hamura R;Taniai T;Horiuchi T;Takada N;Haruki K;Furukawa K;Uwagawa T;Kobayashi H;Ikegami T.
鞘磷脂代谢在细胞膜的形成中起着重要作用，并与癌细胞的恶性潜能和化疗敏感性有关。鞘脂的降解依赖于多种溶酶体葡萄糖苷酶。我们重点研究了酸性β-葡萄糖苷酶，这是一种溶酶体酶，其缺陷与线粒体功能障碍有关。我们分析了GBA在胰腺导管腺癌中的作用。用短干扰RNA(SiRNA)方法检测了人PDAC细胞系(PANC-1、BxPC-3和ASPC-1)在GBA基因敲除条件下的表达。观察PDAC细胞的形态变化、GBA酶活性、GBA蛋白表达、细胞活力、活性氧(ROS)生成、线粒体膜电位(MMP)和吞噬线粒体膜通量。不同细胞系的GBA蛋白水平和酶活性不同。GBA基因敲除可抑制PANC-1和BxPC-3细胞的增殖和诱导细胞凋亡，且GBA酶活性较低。GBA基因敲除也降低了线粒体膜电位，降低了线粒体的清除能力。这损害了线粒体的清除，进一步诱导了PDAC细胞中功能障碍的线粒体积累和ROS的产生，从而诱导了细胞凋亡。GBA抑制和吉西他滨联合应用的抗增殖作用明显高于单用吉西他滨。这些结果表明，抑制GBA具有显著的抗肿瘤作用，可能在临床治疗PDAC方面具有潜在的应用价值。
Sphingolipid metabolism plays an important role in the formation of cellular membranes and is associated with malignant potential and chemosensitivity of cancer cells. Sphingolipid degradation depends on multiple lysosomal glucosidases. We focused on acid β-glucosidase (GBA), a lysosomal enzyme the deficiency of which is related to mitochondrial dysfunction. We analyzed the function of GBA in pancreatic ductal adenocarcinoma (PDAC). Human PDAC cell lines (PANC-1, BxPC-3 and AsPC-1) were examined under conditions of GBA knockdown via the short interfering RNA (siRNA) method. We assessed the morphological changes, GBA enzyme activity, GBA protein expression, cell viability, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) and mitophagy flux of PDAC cells. The GBA protein level and enzyme activity differed among cell lines. GBA knockdown suppressed cell proliferation and induced apoptosis, especially in PANC-1 and BxPC-3 cells, with low GBA enzyme activity. GBA knockdown also decreased the MMP and impaired mitochondrial clearance. This impaired mitochondrial clearance further induced dysfunctional mitochondria accumulation and ROS generation in PDAC cells, inducing apoptosis. The antiproliferative effects of the combination of GBA suppression and gemcitabine were higher than those of gemcitabine alone. These results showed that GBA suppression exerts a significant antitumor effect and may have therapeutic potential in the clinical treatment of PDAC.