SLPI/FBW7/c-Myc Axis Reduces Gemcitabine Sensitivity in PDAC by Enhancing Glycolysis and Impairing NK Cell Immunity

Sep 23, 2026

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor outcomes. Gemcitabine can induce tumor cell death and stimulate NK cell–mediated antitumor immunity, yet its effectiveness remains limited due to insufficient biomarkers that predict gemcitabine resistance. This study investigates whether secretory leukocyte protease inhibitor (SLPI) modulates gemcitabine sensitivity through metabolic and immune pathways. SLPI is upregulated in PDAC and inversely linked to gemcitabine efficacy and survival. Mechanistically, SLPI stabilizes c-Myc by disrupting FBW7-mediated ubiquitination, promoting c-Myc–driven glycolysis and impairing NK cell lysis. In vivo, SLPI knockdown sensitizes gemcitabine treatment and depends partly on NK cell immunity. Overall, SLPI may serve as a biomarker and therapeutic target to improve gemcitabine response in PDAC.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Gemcitabine resistance and need for biomarkers

Glycolysis as a sensitization target

Role of SLPI

Cancer Science ORIGINAL ARTICLE OPEN ACCESS Cell, Molecular, and Stem Cell Biology SLPI/FBW7/c-Myc Axis Reduces Gemcitabine Sensitivity in PDAC by Enhancing Glycolysis and Impairing NK Cell Immunity Haofei Chen1 | Xin Li2 | Weixiong Zhu1 | Yanxi Mu1 | Guoqing Zhang1 | Youheng Zhang1 | Yusheng Cheng2,3 | Wence Zhou1,2,3,4 1The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China | 2Department of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China | 3Gansu Province Hepatobiliary Pancreatic Disease Precision Diagnosis and Treatment Engineering Research Center, Lanzhou University, Lanzhou, China | 4Gansu Province Key Laboratory of Environmental Oncology, the Second Hospital & Clinical Medical School, Lanzhou University, Lan zhou, China Correspondence: Wence Zhou ([zhouwc129@163.com](zhouwc129@163.com)) Received: 26 November 2025 | Revised: 11 February 2026 | Accepted: 10 March 2026 Keywords: gemcitabine | glycolysis | NK cells | PDAC | SLPI ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal prognosis. Although gemcitabine works by directly inducing tumor cell death, as well as activating NK cell-mediated antitumor immunity, its efficacy remains rather unsatisfying. Currently, biomarkers precisely ascertaining gemcitabine resistance in PDAC are unavailable; thus, it is of much urgency to identify biomarkers accurately predicting gemcitabine sensitivity and explore innovative targets for developing sensitization strategy. Secretory leukocyte protease inhibitor (SLPI) is overexpressed in several solid tumors, but its role in PDAC remains unclear. This study aims to elucidate the function and mechanism of SLPI in modulating gemcitabine sensitivity in PDAC. In this study, we found that SLPI was markedly upregulated in PDAC cell lines and tissues, inversely correlating with gemcitabine efficacy and survival outcome of patients. In vitro, SLPI overexpression significantly reduced PDAC cell sensitivity to gemcitabine-induced direct cytotoxicity and NK cell-mediated lysis through enhancing c-Myc-driven glycolysis, whereas SLPI knockdown generated the opposite effects. Mechanistically, SLPI could directly interact with c-Myc protein, which disturbed the binding of E3 ubiquitin ligase FBW7 to c-Myc and thereby prevented ubiquitination-mediated c-Myc degradation, resultantly increasing c-Myc stability and expression. In vivo, SLPI knockdown substantially sensitized gemcitabine treatment to suppress PDAC growth, and this effect was at least partly dependent on NK cell-mediated antitumor immunity. Totally, our findings support that SLPI may serve as a promising biomarker for predicting gemcitabine therapy response, and targeting SLPI may be an effective strategy to improve gemcitabine efficacy in PDAC patients. All procedures involving animals were conducted in compliance with institutional ethics regulations and approved by the Ethics Committee of the Second Hospital of Lanzhou University (Approval No. D2025-434) . | Abbreviations: AUC, Area under the ROC curve; ECAR, extracellular acidification rate; FBW7, F-box/WD repeat-containing protein 7; IC 50, half maximal inhibitory concentration; MDSC, myeloid-derived suppressor cells; MICA/B, major histocompatibility complex class I chain-related molecules A/B; NK cell, natural killer cell; OS, overall survival; PDAC, pancreatic ductal adenocarcinoma; ROS, reactive oxygen species; SLPI, secretory leukocyte protease inhibitor; ULBP2, UL16 binding protein 2.
Haofei Chen and Xin LiContributed equally to this work. | | --- | | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2026 The Author(s). Cancer Science published by J

FAQs

What problem does the study address about gemcitabine in PDAC?

Gemcitabine efficacy in PDAC is unsatisfactory because many patients show poor sensitivity, and there are no available biomarkers that accurately predict gemcitabine resistance. The study targets the urgent need to find predictors and sensitization mechanisms.

How does SLPI affect gemcitabine sensitivity in PDAC cells?

SLPI overexpression reduces PDAC sensitivity to gemcitabine-induced cytotoxicity and NK cell–mediated lysis, while SLPI knockdown produces the opposite effect. This is linked to enhanced c-Myc-driven glycolysis.

What molecular mechanism links SLPI to c-Myc activity?

SLPI directly interacts with c-Myc and interferes with FBW7 binding, preventing ubiquitination-mediated c-Myc degradation. This increases c-Myc stability and expression, promoting glycolysis.

Does SLPI targeting improve gemcitabine treatment in vivo, and what role do NK cells play?

In vivo, SLPI knockdown sensitizes PDAC to gemcitabine and suppresses tumor growth. The sensitization effect is at least partly dependent on NK cell–mediated antitumor immunity.

Sep 23, 2026

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