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PEPT1 is essential for the growth of pancreatic cancer cells: a viable drug target
- Source :
- Biochemical Journal
- Publication Year :
- 2021
- Publisher :
- Portland Press Ltd., 2021.
-
Abstract
- PEPT1 is a proton-coupled peptide transporter that is up-regulated in PDAC cell lines and PDXs, with little expression in the normal pancreas. However, the relevance of this up-regulation to cancer progression and the mechanism of up-regulation have not been investigated. Herein, we show that PEPT1 is not just up-regulated in a large panel of PDAC cell lines and PDXs but is also functional and transport-competent. PEPT2, another proton-coupled peptide transporter, is also overexpressed in PDAC cell lines and PDXs, but is not functional due to its intracellular localization. Using glibenclamide as a pharmacological inhibitor of PEPT1, we demonstrate in cell lines in vitro and mouse xenografts in vivo that inhibition of PEPT1 reduces the proliferation of the cancer cells. These findings are supported by genetic knockdown of PEPT1 with shRNA, wherein the absence of the transporter significantly attenuates the growth of cancer cells, both in vitro and in vivo, suggesting that PEPT1 is critical for the survival of cancer cells. We also establish that the tumor-derived lactic acid (Warburg effect) in the tumor microenvironment supports the transport function of PEPT1 in the maintenance of amino acid nutrition in cancer cells by inducing MMPs and DPPIV to generate peptide substrates for PEPT1 and by generating a H+ gradient across the plasma membrane to energize PEPT1. Taken collectively, these studies demonstrate a functional link between PEPT1 and extracellular protein breakdown in the tumor microenvironment as a key determinant of pancreatic cancer growth, thus identifying PEPT1 as a potential therapeutic target for PDAC.
- Subjects :
- pancreatic cancer
Microbiology
Peptide Transporter 1
Biochemistry
Small hairpin RNA
Mice
Biochemical Techniques & Resources
transmembrane H+ gradient
In vivo
Cell Line, Tumor
Pancreatic cancer
Glyburide
Tumor Microenvironment
medicine
Animals
Humans
Hypoglycemic Agents
PEPT1
Molecular Targeted Therapy
RNA, Small Interfering
Pancreas
Molecular Biology
Research Articles
Cancer
lactate
Tumor microenvironment
Symporters
Chemistry
Cell Biology
medicine.disease
Xenograft Model Antitumor Assays
Warburg effect
Tumor Burden
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms
glibenclamide
Cell culture
Cancer cell
Cancer research
MMPs
Signal Transduction
Subjects
Details
- ISSN :
- 14708728 and 02646021
- Volume :
- 478
- Database :
- OpenAIRE
- Journal :
- Biochemical Journal
- Accession number :
- edsair.doi.dedup.....6d9d8839e66cf966fa6f7589c93dc593
- Full Text :
- https://doi.org/10.1042/bcj20210377