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Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

EMT-Induced Gemcitabine Resistance in Pancreatic Cancer Involves the Functional Loss of Equilibrative Nucleoside Transporter 1

Brenna Weadick, Debasis Nayak, Avinash K. Persaud, Sau Wai Hung, Radhika Raj, Moray J. Campbell, Wei Chen, Junan Li, Terence M. Williams and Rajgopal Govindarajan
Brenna Weadick
1Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, Ohio.
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Debasis Nayak
1Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, Ohio.
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Avinash K. Persaud
1Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, Ohio.
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Sau Wai Hung
2Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia.
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Radhika Raj
1Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, Ohio.
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Moray J. Campbell
1Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, Ohio.
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  • ORCID record for Moray J. Campbell
Wei Chen
3Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
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Junan Li
1Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, Ohio.
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Terence M. Williams
4Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio.
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  • ORCID record for Terence M. Williams
Rajgopal Govindarajan
1Division of Pharmaceutics and Pharmacology, The Ohio State University College of Pharmacy, Columbus, Ohio.
5Translational Therapeutics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
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  • For correspondence: govindarajan.21@osu.edu
DOI: 10.1158/1535-7163.MCT-20-0316 Published February 2021
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Abstract

Epithelial–mesenchymal transition (EMT) in cancer cells drives cancer chemoresistance, yet the molecular events of EMT that underpin the acquisition of chemoresistance are poorly understood. Here, we demonstrate a loss of gemcitabine chemosensitivity facilitated by human equilibrative nucleoside transporter 1 (ENT1) during EMT in pancreatic cancer and identify that cadherin switching from the epithelial (E) to neuronal (N) type, a hallmark of EMT, contributes to this loss. Our findings demonstrate that N-cadherin decreases ENT1 expression, membrane localization, and gemcitabine transport, while E-cadherin augments each of these. Besides E- and N-cadherin, another epithelial cell adhesion molecule, EpCAM, played a more prominent role in determining ENT1 membrane localization. Forced expression of EpCAM opposed cadherin switching with restored ENT1 expression, membrane localization, and gemcitabine transport in EMT-committed pancreatic cancer cells. In gemcitabine-treated mice, EpCAM-positive tumors had high ENT1 expression and reduced metastasis, whereas tumors with N-cadherin expression resisted gemcitabine treatment and formed extensive secondary metastatic nodules. Tissue microarray profiling and multiplexed IHC analysis of pancreatic cancer patient-derived primary tumors revealed EpCAM and ENT1 cell surface coexpression is favored, and ENT1 plasma membrane expression positively predicted median overall survival times in patients treated with adjuvant gemcitabine. Together, our findings identify ENT1 as an inadvertent target of EMT signaling mediated by cadherin switching and provide a mechanism by which mesenchymal pancreatic cancer cells evade gemcitabine therapy during EMT.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:410–22

  • Received April 22, 2020.
  • Revision received September 2, 2020.
  • Accepted November 19, 2020.
  • Published first December 9, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (2)
February 2021
Volume 20, Issue 2
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EMT-Induced Gemcitabine Resistance in Pancreatic Cancer Involves the Functional Loss of Equilibrative Nucleoside Transporter 1
Brenna Weadick, Debasis Nayak, Avinash K. Persaud, Sau Wai Hung, Radhika Raj, Moray J. Campbell, Wei Chen, Junan Li, Terence M. Williams and Rajgopal Govindarajan
Mol Cancer Ther February 1 2021 (20) (2) 410-422; DOI: 10.1158/1535-7163.MCT-20-0316

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EMT-Induced Gemcitabine Resistance in Pancreatic Cancer Involves the Functional Loss of Equilibrative Nucleoside Transporter 1
Brenna Weadick, Debasis Nayak, Avinash K. Persaud, Sau Wai Hung, Radhika Raj, Moray J. Campbell, Wei Chen, Junan Li, Terence M. Williams and Rajgopal Govindarajan
Mol Cancer Ther February 1 2021 (20) (2) 410-422; DOI: 10.1158/1535-7163.MCT-20-0316
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Molecular Cancer Therapeutics
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