美罗昔康 D 通过靶向 XIAP/PARP1 轴抑制胰腺癌细胞生长并诱导细胞凋亡。
Moracin D suppresses cell growth and induces apoptosis via targeting the XIAP/PARP1 axis in pancreatic cancer.
机构信息
State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China; Jinfeng Laboratory, Chongqing 401329, China; Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing 400716, China.
State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China; Jinfeng Laboratory, Chongqing 401329, China; Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing 400716, China.
出版信息
Phytomedicine. 2024 Jun;128:155527. doi: 10.1016/j.phymed.2024.155527. Epub 2024 Mar 11.
BACKGROUND
Pancreatic cancer, a tumor with a high metastasis rate and poor prognosis, is among the deadliest human malignancies. Investigating effective drugs for their treatment is imperative. Moracin D, a natural benzofuran compound isolated from Morus alba L., shows anti-inflammation and anti-breast cancer properties and is effective against Alzheimer's disease. However, the effect and mechanism of Moracin D action in pancreatic cancer remain obscure.
PURPOSE
To investigate the function and molecular mechanism of Moracin D action in repressing the malignant progression of pancreatic cancer.
METHODS
Pancreatic cancer cells were treated with Moracin D, and cell proliferation was evaluated by cell counting kit-8 (CCK-8) and immunofluorescence assays. The clonogenicity of pancreatic cancer cells was assessed based on plate colony formation and soft agar assay. Flow cytometry was used to detect cell apoptosis. The expression of proteins related to the apoptosis pathway was determined by Western blot analysis. Moracin D and XIAP were subjected to docking by auto-dock molecular docking analysis. Ubiquitination levels of XIAP and the interaction of XIAP and PARP1 were assessed by co-immunoprecipitation analysis. Moracin D's effects on tumorigenicity were assessed by a tumor xenograft assay.
RESULTS
Moracin D inhibited cell proliferation, induced cell apoptosis, and regulated the protein expression of molecules involved in caspase-dependent apoptosis pathways. Moracin D suppressed clonogenicity and tumorigenesis of pancreatic cancer cells. Mechanistically, XIAP could interact with PARP1 and stabilize PARP1 by controlling its ubiquitination levels. Moracin D diminished the stability of XIAP and decreased the expression of XIAP by promoting proteasome-dependent XIAP degradation, further blocking the XIAP/PARP1 axis and repressing the progression of pancreatic cancer. Moracin D could dramatically improve the chemosensitivity of gemcitabine in pancreatic cancer cells.
CONCLUSION
Moracin D repressed cell growth and tumorigenesis, induced cell apoptosis, and enhanced the chemosensitivity of gemcitabine through the XIAP/PARP1 axis in pancreatic cancer. Moracin D is a potential therapeutic agent or adjuvant for pancreatic cancer.
背景
胰腺癌是一种转移率高、预后差的肿瘤，是人类最致命的恶性肿瘤之一。研究有效的治疗药物是当务之急。从桑白皮中分离得到的天然苯并呋喃类化合物莫那可林 D 具有抗炎和抗乳腺癌作用，对阿尔茨海默病也有疗效。然而，莫那可林 D 在胰腺癌中的作用和机制尚不清楚。
目的
研究莫那可林 D 抑制胰腺癌恶性进展的作用及其分子机制。
方法
用莫那可林 D 处理胰腺癌细胞，用细胞计数试剂盒-8（CCK-8）和免疫荧光法评估细胞增殖。根据平板集落形成和软琼脂实验评估胰腺癌细胞的克隆形成能力。用流式细胞术检测细胞凋亡。用 Western blot 分析检测与细胞凋亡途径相关的蛋白表达。用自动对接分子对接分析研究莫那可林 D 和 XIAP 的对接情况。用 co-immunoprecipitation 分析评估 XIAP 的泛素化水平和 XIAP 与 PARP1 的相互作用。用肿瘤异种移植实验评估莫那可林 D 的抑瘤作用。
结果
莫那可林 D 抑制细胞增殖，诱导细胞凋亡，并调节 caspase 依赖性细胞凋亡途径相关分子的蛋白表达。莫那可林 D 抑制胰腺癌细胞的克隆形成和致瘤性。机制上，XIAP 可通过控制其泛素化水平与 PARP1 相互作用并稳定 PARP1。莫那可林 D 通过促进 XIAP 的蛋白酶体依赖性降解，降低 XIAP 的稳定性和表达，从而削弱 XIAP/PARP1 轴，抑制胰腺癌的进展。莫那可林 D 可显著提高胰腺癌细胞对吉西他滨的化疗敏感性。
结论
莫那可林 D 通过 XIAP/PARP1 轴抑制胰腺癌细胞生长和肿瘤发生，诱导细胞凋亡，并增强吉西他滨的化疗敏感性。莫那可林 D 是治疗胰腺癌的潜在药物或辅助药物。
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