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Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression

56 Pages Posted: 10 Jun 2019 Sneak Peek Status: Review Complete

See all articles by Charlotte Baker

Charlotte Baker

University of Lisbon - Institute of Molecular Medicine

Tiago Rodrigues

University of Lisbon - Institute of Molecular Medicine

Ruth A. Pumroy

University of Pennsylvania - Department of Systems Pharmacology and Translational Therapeutics

João Conde

University of Lisbon - Instituto de Medicina Molecular (iMM)

Daniel Picard

German Cancer Research Center (DKFZ)

Marta C. Marques

University of Lisbon - Instituto de Medicina Molecular (iMM)

Bernardo P. de Almeida

University of Lisbon - Instituto de Medicina Molecular (iMM)

Amrita Samanta

University of Pennsylvania - Department of Systems Pharmacology and Translational Therapeutics

Florian Sieglitz

University of Lisbon - Instituto de Medicina Molecular (iMM)

Maike Langini

German Cancer Research Center (DKFZ)

Marc Remke

German Cancer Research Center (DKFZ)

Rafael Roque

Centro Hospitalar Universitário Lisboa Norte (CHLN)

Francisco Corzana

University of La Rioja

Cláudia C. Faria

University of Lisbon - Instituto de Medicina Molecular (iMM)

Tânia Carvalho

University of Lisbon - Instituto de Medicina Molecular (iMM)

Nuno L. Barbosa-Morais

University of Lisbon - Instituto de Medicina Molecular (iMM)

Vera Y. Moiseenkova-Bell

University of Pennsylvania - Department of Systems Pharmacology and Translational Therapeutics

Gonçalo J. L. Bernardes

University of Lisbon - Instituto de Medicina Molecular (iMM)

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Abstract

The use of machine learning to identify biological targets for natural products with anticancer properties and unknown modes of action is gaining momentum. We used machine intelligence to deconvolute the phenotypic effects of Piperlongumine (PL) and establish a link to allosteric modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to an allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Down-regulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression and poor prognosis. We obtained tumor remission in a murine model of orthotopic GBM by formulating PL for sustained local therapy. Our strategy is broadly applicable and leverages data-motivated research hypotheses for the discovery of new biology and therapeutics.

Keywords: piperlongumine, transient receptor potential vanilloid channel, chemical biology, cryo-electron microscopy, glioblastoma

Suggested Citation

Baker, Charlotte and Rodrigues, Tiago and Pumroy, Ruth A. and Conde, João and Picard, Daniel and Marques, Marta C. and de Almeida, Bernardo P. and Samanta, Amrita and Sieglitz, Florian and Langini, Maike and Remke, Marc and Roque, Rafael and Corzana, Francisco and Faria, Cláudia C. and Carvalho, Tânia and Barbosa-Morais, Nuno L. and Moiseenkova-Bell, Vera Y. and Bernardes, Gonçalo J. L., Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression (June 10, 2019). CELL-D-19-01528. Available at SSRN: https://ssrn.com/abstract=3402071 or http://dx.doi.org/10.2139/ssrn.3402071
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Charlotte Baker

University of Lisbon - Institute of Molecular Medicine

R. Branca Edmée Marques
Lisbon, 1600-276
Portugal

Tiago Rodrigues

University of Lisbon - Institute of Molecular Medicine

R. Branca Edmée Marques
Lisbon, 1600-276
Portugal

Ruth A. Pumroy

University of Pennsylvania - Department of Systems Pharmacology and Translational Therapeutics ( email )

United States

João Conde

University of Lisbon - Instituto de Medicina Molecular (iMM) ( email )

Av. Professor Egas Moniz
Lisboa, 1649-028
Portugal

Daniel Picard

German Cancer Research Center (DKFZ) ( email )

Im Neuenheimer Feld 280
Heidelberg, 69120
Germany

Marta C. Marques

University of Lisbon - Instituto de Medicina Molecular (iMM) ( email )

Av. Professor Egas Moniz
Lisboa, 1649-028
Portugal

Bernardo P. De Almeida

University of Lisbon - Instituto de Medicina Molecular (iMM)

Av. Professor Egas Moniz
Lisboa, 1649-028
Portugal

Amrita Samanta

University of Pennsylvania - Department of Systems Pharmacology and Translational Therapeutics ( email )

United States

Florian Sieglitz

University of Lisbon - Instituto de Medicina Molecular (iMM) ( email )

Av. Professor Egas Moniz
Lisboa, 1649-028
Portugal

Maike Langini

German Cancer Research Center (DKFZ) ( email )

Im Neuenheimer Feld 280
Heidelberg, 69120
Germany

Marc Remke

German Cancer Research Center (DKFZ) ( email )

Im Neuenheimer Feld 280
Heidelberg, 69120
Germany

Rafael Roque

Centro Hospitalar Universitário Lisboa Norte (CHLN) ( email )

Portugal

Francisco Corzana

University of La Rioja ( email )

Cigueña 60
Logroño, La Rioja 26004
United States

Cláudia C. Faria

University of Lisbon - Instituto de Medicina Molecular (iMM) ( email )

Av. Professor Egas Moniz
Lisboa, 1649-028
Portugal

Tânia Carvalho

University of Lisbon - Instituto de Medicina Molecular (iMM) ( email )

Av. Professor Egas Moniz
Lisboa, 1649-028
Portugal

Nuno L. Barbosa-Morais

University of Lisbon - Instituto de Medicina Molecular (iMM) ( email )

Av. Professor Egas Moniz
Lisboa, 1649-028
Portugal

Vera Y. Moiseenkova-Bell

University of Pennsylvania - Department of Systems Pharmacology and Translational Therapeutics ( email )

United States

Gonçalo J. L. Bernardes (Contact Author)

University of Lisbon - Instituto de Medicina Molecular (iMM) ( email )

Av. Professor Egas Moniz
Lisboa, 1649-028
Portugal

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