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Peer-reviewedCC BYFrontiers in pharmacology

CGRP remodels the acidic microenvironment and promotes pancreatic carcinoma progression by regulating NHE1 and CA9

  • Sa Liu1
  • Shanshan Wei1
  • Taoli Sun2
  • Dai Li3
  • Yuanjian Li4
  • Bikui Zhang1
  • Yangchun Xie5
  • Wenqun Li1
5 affiliations
  1. 1Department of Pharmacy, The Second Xiangya Hospital, Central South University , ,
  2. 2Institute of Dietotherapy and Herbal Medicinal Diet, Hunan Academy of Chinese Medicine , ,
  3. 3Phase I Clinical Research Center, Xiangya Hospital, Central South University , ,
  4. 4Department of Pharmacology, School of Pharmaceutical Science, Central South University , ,
  5. 5Department of Oncology, The Second Xiangya Hospital, Central South University , ,
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Abstract

Introduction: Neurons can regulate cancer cells to modulate their survival and growth, the interplay between calcitonin gene-related peptide (CGRP) and the acidic tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) remains unknown.

Methods and Results: Here, we reported that CGRP expression and neuronal activation markers p-ERK/p-CREB were significantly elevated in PDAC tissues. Exogenous CGRP promoted PANC02 cell proliferation and migration, whereas CGRP knockout suppressed orthotopic tumor growth. Mechanistically, CGRP upregulated the proton transporters NHE1 and CA9, facilitating H ⁺ efflux and reducing extracellular pH, thereby exacerbating TME acidification. Clinical analysis revealed that high expression of NHE1 and CA9 correlated with poor prognosis in PDAC patients. Rimegepant, a CGRP receptor antagonist, inhibited orthotopic tumor growth and exhibited synergistic effects with gemcitabine.

Conclusion and Discussion: In conclusion, our findings uncover a functional connection between CGRPergic sensory neurons and the acidic TME, identifying the CGRP signaling pathway as a potential therapeutic target for PDAC. Despite these findings, the mechanistic conclusions remain correlative and require further validation, and the generalizability to human PDAC warrants future investigation.

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Cite

BibTeXRIS
BibTeX
@article{liu2026cgrp,
  title = {{CGRP remodels the acidic microenvironment and promotes pancreatic carcinoma progression by regulating NHE1 and CA9}},
  author = {Sa Liu and Shanshan Wei and Taoli Sun and Dai Li and Yuanjian Li and Bikui Zhang and Yangchun Xie and Wenqun Li},
  journal = {Frontiers in pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1928812},
  url = {https://europepmc.org/article/PMC/PMC13669720},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - CGRP remodels the acidic microenvironment and promotes pancreatic carcinoma progression by regulating NHE1 and CA9
AU  - Sa Liu
AU  - Shanshan Wei
AU  - Taoli Sun
AU  - Dai Li
AU  - Yuanjian Li
AU  - Bikui Zhang
AU  - Yangchun Xie
AU  - Wenqun Li
PY  - 2026
DA  - 2026/10/01
JO  - Frontiers in pharmacology
DO  - 10.3389/fphar.2026.1928812
UR  - https://europepmc.org/article/PMC/PMC13669720
AB  - Introduction: Neurons can regulate cancer cells to modulate their survival and growth, the interplay between calcitonin gene-related peptide (CGRP) and the acidic tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) remains unknown.  Methods and Results: Here, we reported that CGRP expression and neuronal activation markers p-ERK/p-CREB were significantly elevated in PDAC tissues. Exogenous CGRP promoted PANC02 cell proliferation and migration, whereas CGRP knockout suppressed orthotopic tumor growth. Mechanistically, CGRP upregulated the proton transporters NHE1 and CA9, facilitating H ⁺ efflux and reducing extracellular pH, thereby exacerbating TME acidification. Clinical analysis revealed that high expression of NHE1 and CA9 correlated with poor prognosis in PDAC patients. Rimegepant, a CGRP receptor antagonist, inhibited orthotopic tumor growth and exhibited synergistic effects with gemcitabine.  Conclusion and Discussion: In conclusion, our findings uncover a functional connection between CGRPergic sensory neurons and the acidic TME, identifying the CGRP signaling pathway as a potential therapeutic target for PDAC. Despite these findings, the mechanistic conclusions remain correlative and require further validation, and the generalizability to human PDAC warrants future investigation.
SN  - 1663-9812
ER  -