<br>Prunetrin 通过 Akt/mTOR/MAPK 通路诱导肝细胞癌细胞 G2/M 细胞周期停滞和凋亡的研究,Biomedicine & Pharmacotherapy

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Prunetrin 通过 Akt/mTOR/MAPK 通路诱导肝细胞癌细胞 G2/M 细胞周期停滞和凋亡的研究
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2024-03-28 , DOI: 10.1016/j.biopha.2024.116483
Abuyaseer Abusaliya ₁ , Pritam Bhagwan Bhosale ₁ , Hun Hwan Kim ₁ , Min Yeong Park ₁ , Se Hyo Jeong ₁ , Sijoon Lee ₂ , Gon Sup Kim ₁

Affiliation

肝细胞癌（HCC）是导致死亡的主要原因，尽管总体生存率最近取得了进步，但预后仍然令人沮丧。 Prunetin 4-O-glucoside（Prunetrin 或 PUR）是一种源自李属植物的活性化合物，人们对其对 HepG2 和 Huh7 细胞的影响进行了探索。细胞毒性评估显示两种细胞系的细胞活力均显着降低，同时对 HaCaT 细胞表现出无毒性。集落形成研究强调了 PUR 对细胞增殖的抑制作用，且呈剂量依赖性。从机制上讲，PUR 下调细胞周期蛋白（CDC25c、Cdk1/CDC2 和 Cyclin B1），诱导 G2/M 期停滞，流式细胞术证实了这一点。蛋白质印迹分析显示 PARP 和 caspase 3 的剂量依赖性裂解，表明细胞凋亡。使用细胞凋亡抑制剂 z-vmd-fmk 进行治疗提供了 PUR 诱导细胞凋亡的证据。膜联蛋白V和PI流式细胞术进一步证实了细胞凋亡的诱导。 cleaved-caspase 9 和促凋亡蛋白 Bak 的表达增强，同时抗凋亡 Bcl-xL 减少，证实了 PUR 诱导内在凋亡。此外，PUR 激活了 MAPK 通路，两种细胞系中磷酸化 p38 和磷酸化 ERK 表达升高证明了这一点。值得注意的是，mTOR 和 Akt 表达的浓度依赖性下降表明 PUR 对 HepG2 和 Huh7 细胞中 Akt/mTOR 通路的抑制。这些发现阐明了 PUR 的多方面影响，揭示了其通过调节细胞周期、细胞凋亡和关键信号通路作为针对 HepG2 和 Huh7 细胞的有前途的治疗剂的潜力。

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Investigation of prunetrin induced G2/M cell cycle arrest and apoptosis via Akt/mTOR/MAPK pathways in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) stands as a leading cause of mortality, and despite recent advancements in the overall survival rates, the prognosis remains dismal. Prunetin 4-O-glucoside (Prunetrin or PUR), an active compound derived from Prunus sp., was explored for its impact on HepG2 and Huh7 cells. The cytotoxicity assessment revealed a notable reduction in cell viability in both cell lines, while exhibiting non-toxicity towards HaCaT cells. Colony formation studies underscored PUR's inhibitory effect on cell proliferation, dose-dependently. Mechanistically, PUR downregulated cell cycle proteins (CDC25c, Cdk1/CDC2, and Cyclin B1), inducing G2/M phase arrest, corroborated by flow cytometry. Western blot analyses exhibited dose-dependent cleavages of PARP and caspase 3, indicative of apoptosis. Treatment with the apoptotic inhibitor z-vmd-fmk provided evidence of PUR-induced apoptosis. Annexin V and PI flow cytometry further affirmed apoptotic induction. Enhanced expression of cleaved-caspase 9 and the pro-apoptotic protein Bak, coupled with reduced anti-apoptotic Bcl-xL, and affirmed PUR's induction of intrinsic apoptosis. Additionally, PUR activated the MAPK pathway, evidenced by elevated phospho p38 and phospho ERK expressions in both cell lines. Notably, a concentration-dependent decrease in mTOR and Akt expressions indicated PUR's inhibition of the Akt/mTOR pathway in HepG2 and Huh7 cells. These findings illuminate PUR's multifaceted impact, revealing its potential as a promising therapeutic agent against HepG2 and Huh7 cells through modulation of cell cycle, apoptosis, and key signaling pathways.

更新日期：2024-03-28

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