Targeting SERPINB5 and MSLN for Pancreatic Cancer Therapy
- 1Department of Pharmacology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
- 2Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
Abstract
Background/Objectives: Pancreatic cancer (PC) is a leading cause of cancer-related death in the United States and lacks efficient therapeutic options. Serine peptidase inhibitor, clade B, member 5 (SERPINB5) is non-inhibitory toward serine proteases, yet it has diverse biological functions, including regulating cell migration, cell death, gene expression, and stress responses. Mesothelin (MSLN) is a tumor-associated antigen that is broadly overexpressed on various malignant tumor cells and plays a crucial role in promoting proliferation, invasion, and metastasis. Methods: We integrated public database analyses, cell-line screening, gene knockdown and overexpression, immunoblotting, cell viability and apoptosis assays, flow cytometry, chromatin immunoprecipitation paired with quantitative PCR (ChIP-qPCR), and chimeric antigen receptor (CAR) T-cell therapy to investigate SERPINB5 and MSLN functions, developing a novel and effective therapeutic strategy for patients with pancreatic cancer. Results: Both SERPINB5 and MSLN are highly expressed and negatively associated with the overall survival of PC patients. Our mechanistic study suggests that SERPINB5 negatively regulates the mitochondrial protein dehydrogenase/reductase 2 (DHRS2) to promote PC cell survival; consequently, SERPINB5 depletion induces PC cell apoptosis. Of note, SERPINB5 depletion increases MSLN transcription by enhancing c-Myc binding to the MSLN promoter region, which in turn suppresses the mitochondrial protein DHRS2 and leads to resistance to apoptosis in PC cells. Our genetic ablation study shows that SERPINB5 and MSLN are critical for PC cell survival, and that depleting both proteins synergistically induces PC cell apoptosis. Gemcitabine (GEM) is a standard chemotherapy drug for PC treatment. Our study shows that SERPINB5-high PC cells display greater sensitivity to GEM than SERPINB5-low PC cells. GEM treatment increases mitochondrial DHRS2 protein expression, similar to the effect of SERPINB5 knockdown, whereas upregulated MSLN confers apoptotic resistance by decreasing DHRS2 levels. Conclusions: Our in vitro study demonstrates that sequential treatment with GEM followed by anti-MSLN chimeric antigen receptor (CAR)-T cells is an effective and promising strategy for patients with pancreatic cancer. Future studies using mouse models may validate the efficacy of this sequential treatment strategy in vivo.
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BibTeX
@article{sun2026targeting,
title = {{Targeting SERPINB5 and MSLN for Pancreatic Cancer Therapy}},
author = {Jinghui Sun and Lingling Liu and Rhyston Broadhurst and David Wang and Anand Mehta and Denis C. Guttridge and Leonardo M. R. Ferreira and Haizhen Wang and Xueliang Gao},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18193242},
url = {https://europepmc.org/article/PMC/PMC13664176},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting SERPINB5 and MSLN for Pancreatic Cancer Therapy
AU - Jinghui Sun
AU - Lingling Liu
AU - Rhyston Broadhurst
AU - David Wang
AU - Anand Mehta
AU - Denis C. Guttridge
AU - Leonardo M. R. Ferreira
AU - Haizhen Wang
AU - Xueliang Gao
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18193242
UR - https://europepmc.org/article/PMC/PMC13664176
AB - Background/Objectives: Pancreatic cancer (PC) is a leading cause of cancer-related death in the United States and lacks efficient therapeutic options. Serine peptidase inhibitor, clade B, member 5 (SERPINB5) is non-inhibitory toward serine proteases, yet it has diverse biological functions, including regulating cell migration, cell death, gene expression, and stress responses. Mesothelin (MSLN) is a tumor-associated antigen that is broadly overexpressed on various malignant tumor cells and plays a crucial role in promoting proliferation, invasion, and metastasis. Methods: We integrated public database analyses, cell-line screening, gene knockdown and overexpression, immunoblotting, cell viability and apoptosis assays, flow cytometry, chromatin immunoprecipitation paired with quantitative PCR (ChIP-qPCR), and chimeric antigen receptor (CAR) T-cell therapy to investigate SERPINB5 and MSLN functions, developing a novel and effective therapeutic strategy for patients with pancreatic cancer. Results: Both SERPINB5 and MSLN are highly expressed and negatively associated with the overall survival of PC patients. Our mechanistic study suggests that SERPINB5 negatively regulates the mitochondrial protein dehydrogenase/reductase 2 (DHRS2) to promote PC cell survival; consequently, SERPINB5 depletion induces PC cell apoptosis. Of note, SERPINB5 depletion increases MSLN transcription by enhancing c-Myc binding to the MSLN promoter region, which in turn suppresses the mitochondrial protein DHRS2 and leads to resistance to apoptosis in PC cells. Our genetic ablation study shows that SERPINB5 and MSLN are critical for PC cell survival, and that depleting both proteins synergistically induces PC cell apoptosis. Gemcitabine (GEM) is a standard chemotherapy drug for PC treatment. Our study shows that SERPINB5-high PC cells display greater sensitivity to GEM than SERPINB5-low PC cells. GEM treatment increases mitochondrial DHRS2 protein expression, similar to the effect of SERPINB5 knockdown, whereas upregulated MSLN confers apoptotic resistance by decreasing DHRS2 levels. Conclusions: Our in vitro study demonstrates that sequential treatment with GEM followed by anti-MSLN chimeric antigen receptor (CAR)-T cells is an effective and promising strategy for patients with pancreatic cancer. Future studies using mouse models may validate the efficacy of this sequential treatment strategy in vivo.
SN - 2072-6694
ER -