Inhibition of Clusterin Represses Proliferation by Inducing Cellular Senescence in Pancreatic Cancer
Inhibition of Clusterin Represses Proliferation by Inducing Cellular Senescence in Pancreatic Cancer
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DOI：
10.1245/s10434-022-11668-0
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发表时间：
2022-04-10
影响因子：
3.7
通讯作者：
Eguchi, Hidetoshi
中科院分区：
文献类型：
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作者：
Mitsufuji, Suguru;Iwagami, Yoshifumi;Eguchi, Hidetoshi
背景胰腺导管腺癌（PDAC）的治疗效果不理想，迫切需要寻找新的治疗靶点。已经进行了针对丛生蛋白（CLU）表达的反义寡核苷酸的临床研究，并在其他癌症中显示出疗效。本研究旨在探讨CLU在PDAC中的作用及其机制，以期为现有药物的临床应用提供参考。我们敲低了PDAC细胞中的CLU，并评估了细胞增殖的变化。为了阐明这些变化的机制，我们进行了蛋白质印迹分析，细胞周期测定，和衰老相关的β-半乳糖苷酶（SA-β-gal）染色。为探讨CLU的临床意义，采用免疫组织化学方法检测术前未经化疗的PDAC患者的肿瘤组织中CLU的表达。CLU的敲低显著降低细胞增殖，不诱导凋亡，但通过增加G1期和SA-β-gal染色阳性细胞的百分比诱导细胞衰老。DNA损伤的标记物，如γ H2 AX和与细胞衰老相关的因子，如p21和衰老相关的分泌表型，通过敲低CLU而上调。CLU在PDAC切除标本中的表达定位于肿瘤细胞的胞浆中，低CLU组的无复发生存率和总生存率显著高于高CLU组。我们确定，CLU抑制导致PDAC中的细胞衰老。我们的研究结果表明，CLU是一个新的治疗靶点，有助于PDAC的预后诱导细胞衰老。
Background. The outcome of pancreatic ductal adenocarcinoma (PDAC) is unsatisfactory, and the identification of novel therapeutic targets is urgently needed. Clinical studies on the antisense oligonucleotide that targets clusterin (CLU) expression have been conducted and have shown efficacy in other cancers. We aimed to investigate the effects of CLU in PDAC and the underlying mechanisms with a view to the clinical application of existing drugs.Methods. We knocked down CLU in PDAC cells and evaluated changes in cell proliferation. To elucidate the mechanism responsible for these changes, we performed western blot analysis, cell cycle assay, and senescence-associated beta-galactosidase (SA-beta-gal) staining. To evaluate the clinical significance of CLU, immunohistochemistry was performed, and CLU expression was analyzed in specimens resected from PDAC patients not treated with preoperative chemotherapy.Results. Knockdown of CLU significantly decreased cell proliferation and did not induce apoptosis, but did induce cellular senescence by increasing the percentage of G1-phase and SA-beta-gal staining-positive cells. A marker of DNA damage such as gamma H2AX and factors related to cellular senescence, such as p21 and the senescence-associated secretory phenotype, were upregulated by knockdown of CLU. CLU expression in resected PDAC specimens was located in the cytoplasm of tumor cells and revealed significantly better recurrence-free survival and overall survival in the CLU-low group than in the CLU-high group.Conclusions. We identified that CLU inhibition leads to cellular senescence in PDAC. Our findings suggest that CLU is a novel therapeutic target that contributes to the prognosis of PDAC by inducing cellular senescence.