Open Access

ARTICLE

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

Xinxin Hu^1,2,#, Yuye Xue^3,#, Fei Fang⁴, Jie Li², Xiaofeng Yuan², Guang Cheng⁵, Hailong Yuan³, Yongqiang Zhang², Yuefei Zhou⁵, Shuangwu Yang⁵, Pengcheng Qiu^2,*, Yunyang Lu², Haifeng Tang^2,*

1 School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
2 Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Fourth Military Medical University, Xi’an, 710032, China
3 Department of Pharmacy, Air Force Medical Center, PLA, The Fourth Military Medical University, Beijing, 100142, China
4 Department of Central Laboratory, The First Affiliated Hospital of Northwestern University, The First Hospital of Xi’an, Xi’an, 710069, China
5 Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, The Fourth Military Medical University, Xi’an, 710032, China

* Corresponding Authors: Pengcheng Qiu. Email: ; Haifeng Tang. Email:
# These authors contributed equally to this work

(This article belongs to the Special Issue: New Insights in Drug Resistance of Cancer Therapy: A New Wine in an Old Bottle)

Oncology Research 2025, 33(9), 2491-2506. https://doi.org/10.32604/or.2025.064454

Received 16 February 2025; Accepted 28 May 2025; Issue published 28 August 2025

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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