@Article{biocell.2025.062144,
AUTHOR = {Jae Hyeong Kim, Yuna Youn, Jin-Hyeok Hwang},
TITLE = {<i>SLFN11</i> Deficiency-Induced Gemcitabine Resistance Is Overcome by Agents Targeting the DNA Damage Response in Pancreatic Cancer Cells},
JOURNAL = {BIOCELL},
VOLUME = {49},
YEAR = {2025},
NUMBER = {4},
PAGES = {681--700},
URL = {http://www.techscience.com/biocell/v49n4/60781},
ISSN = {1667-5746},
ABSTRACT = { <b>Objectives:</b> <i>SLFN11</i> (Schlafen-11) enhances sensitivity to DNA-damaging agents (DDAs) and DNA damage response (DDR) inhibitors in various cancer types. However, its function in pancreatic cancer (PC) remains largely unknown. This research aims to investigate the expression patterns of <i>SLFN11</i> and other <i>SLFN</i> family members in PC and their correlation with drug sensitivity. <b>Methods:</b> <i>SLFN11</i> expression and genetic alterations were analyzed using publicly available datasets (TCGA and GTEx). Functional studies, including cell cycle, apoptosis assays, and proliferation assays, were performed in <i>SLFN11</i>-knockdown and <i>SLFN11</i>-knockout (KO) PC cells. The relationship between <i>SLFN11</i> expression and drug responsiveness was assessed via the CellMiner Cross-Database. <b>Results:</b> Analysis of multiple public datasets demonstrated that elevated <i>SLFN11</i> expression is significantly linked with poor survival outcomes in PC, supporting its function as a predictive marker. Functional assays in PC cell lines demonstrated that <i>SLFN11</i> knockdown disrupted G1 phase progression and increased apoptosis, indicating its involvement in tumor cell survival. Moreover, while elevated <i>SLFN11</i> expression correlated with improved sensitivity to gemcitabine in some cell lines, CRISPR/Cas9-mediated <i>SLFN11</i> knockout resulted in notable gemcitabine resistance. Importantly, this resistance was partially reversed when gemcitabine was combined with cisplatin and DDR inhibitors (Poly (ADP-ribose) polymerase (PARP), ataxia telangiectasia and Rad3 related (ATR), and Wee1 inhibitors), suggesting that <i>SLFN11</i> modulates the reaction to both DNA-damaging agents and DDR-targeted therapies. <b>Conclusion:</b> Our findings indicate that <i>SLFN11</i> plays a dual role in PC: as a prognostic marker, with high expression linked to poor clinical outcomes, and as a predictor of drug sensitivity, where its presence is associated with increased gemcitabine efficacy. However, the development of chemoresistance upon <i>SLFN11</i> loss (and its partial reversal by DDR inhibitors) highlights the complexity of its function. These results underscore that <i>SLFN11</i> expression alone may not fully determine gemcitabine response, and additional factors are likely involved. Further clinical validation is therefore essential to establish <i>SLFN11</i> as a reliable biomarker for guiding DDR-targeted therapeutic strategies in PC.},
DOI = {10.32604/biocell.2025.062144}
}