SORBS1 Knockdown Resists S/G2 Arrest and Apoptosis Caused by Polyphyllin H-Induced DNA Damage in Pancreatic Cancer.

IF 4.1 4区医学 Q3 ONCOLOGY

Oncology Research Pub Date : 2025-08-28 eCollection Date: 2025-01-01 DOI:10.32604/or.2025.064454

Xinxin Hu, Yuye Xue, Fei Fang, Jie Li, Xiaofeng Yuan, Guang Cheng, Hailong Yuan, Yongqiang Zhang, Yuefei Zhou, Shuangwu Yang, Pengcheng Qiu, Yunyang Lu, Haifeng Tang

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引用次数: 0

Abstract

Objectives: The Sorbin and SH3 domain containing 1 (SORBS1), a protein linked to insulin signaling CBL interaction, was investigated for its role in pancreatic cancer apoptosis. This study explored polyphyllin H (PPH)'s ability to restore SORBS1-knockdown-mediated repair functions.

Methods: PANC-1 cells were divided into Blank, overexpression (OE), and knockdown groups. CCK-8 assays assessed proliferation and drug toxicity. Western blot and flow cytometry analyzed SORBS1 levels and PPH effects. Comet assays quantified DNA damage. Subcutaneous xenograft tumors in nude mice (Blank vs. knockdown) were treated with PPH to evaluate in vivo efficacy. SORBS1-H2AX gene correlation was analyzed Spearman rank clustering (p < 0.05).

Results: PPH suppressed pancreatic cancer growth in vitro/vivo, but its efficacy was attenuated by SORBS1 downregulation. Clinically, low SORBS1 correlated with poor prognosis. SORBS1 knockdown promoted tumor proliferation and reduced PPH-induced apoptosis. While PPH decreased tumor volume in both Blank and knockdown groups compared to controls, SORBS1 knockdown diminished PPH's inhibitory effects. Mechanistically, SORBS1 depletion mitigated PPH-triggered DNA damage, circumventing G2/M arrest by modulating WEE1, Cyclin A2, CDK1, and Cyclin B1, thereby impairing apoptosis.

Conclusion: SORBS1 knockdown counteracts PPH-mediated S/G2 arrest and apoptosis by alleviating DNA damage in pancreatic cancer. These findings highlight SORBS1 as a critical modulator of PPH's therapeutic potential, linking its expression to chemoresistance mechanisms.

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SORBS1敲低抵抗多叶素h诱导的胰腺癌DNA损伤引起的S/G2阻滞和凋亡

目的：研究Sorbin和SH3结构域1 (SORBS1)，一种与胰岛素信号CBL相互作用相关的蛋白，在胰腺癌细胞凋亡中的作用。本研究探讨了polyphyllin H （PPH）恢复sorbs1敲低介导的修复功能的能力。方法：将PANC-1细胞分为空白组、过表达组和敲低组。CCK-8检测评估细胞增殖和药物毒性。Western blot和流式细胞术分析SORBS1水平和PPH效应。彗星分析定量DNA损伤。用PPH治疗裸鼠皮下异种移植瘤（空白与敲除），评价其体内疗效。SORBS1-H2AX基因相关性采用Spearman秩聚类分析（p < 0.05）。结果：PPH在体外/体内均能抑制胰腺癌的生长，但其作用因SORBS1下调而减弱。临床上，SORBS1水平低与预后不良相关。SORBS1敲低可促进肿瘤增殖，减少pph诱导的细胞凋亡。与对照组相比，PPH在空白组和敲低组中均能减少肿瘤体积，而SORBS1敲低组则会减弱PPH的抑制作用。机制上，SORBS1缺失减轻了pph引发的DNA损伤，通过调节WEE1、Cyclin A2、CDK1和Cyclin B1来规避G2/M阻滞，从而损害细胞凋亡。结论：SORBS1敲低可通过减轻胰腺癌DNA损伤来抵消pph介导的S/G2阻滞和细胞凋亡。这些发现强调了SORBS1作为PPH治疗潜力的关键调节剂，将其表达与化疗耐药机制联系起来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncology Research 医学-肿瘤学

CiteScore

4.40

自引率

0.00%

发文量

审稿时长

3 months

期刊介绍： Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.