The protein hCNT1, which plays a major role in nucleoside transport, may have other biological functions that may affect cancer cells physiology, apart from their transport function. This is the main conclusion of the new scientific work published on the journal Cell Death and Disease. The paper is signed by a University of Barcelona research group composed by Marçal Pastor Anglada, Sandra Pérez Torras, Anna Vidal Pla, Pedro Cano Soldado, Isabel Huber Ruano, and Adela Mazo, experts from the Department of Biochemistry and Molecular Biology, the Institute of Biomedicine of the UB (IBUB), and the Biomedical Research Networking Center on Hepatic and Digestive Diseases (CIBERehd).
Transporters, the gateway into cells
Nucleosides transporters are integral membrane proteins able to uptake and transport nucleosides, which are biomolecules formed by attaching a sugar and a nitrogenous base that take part in several cellular processes (nucleic acids synthesis, energy metabolism, etc.). These transporters are also the gateway into the cell for many compounds similar to nucleosides, for instance, cytotoxic agents with antitumor and antiviral activity.
Professor Marçal Pastor Anglada, research director and head of the Consolidated Research Group on Molecular Pharmacology and Experimental Therapies (MPET) of the UB, states that "the role of nucleoside-derived drugs in cancer and viral diseases chemotherapy has been studied for years. On the contrary, we are recently studying the biological activity of nucleoside transporters, particularly drug transport in order to design new cancer treatments".
Many nucleoside and similar drug transporters show different expression patterns in healthy tissues and cancer cells. Once in the cell, drugs transported can interfere in the routes bound to cell proliferation (tumours) or virus replication. To be exact, proteins hCNT are a nucleoside transporter family which shows high affinity for many drugs. They are expressed on many target cells and on all epithelial barriers which are determinant in pharmacokinetics intestinal epithelium, liver, kidney, and in the placenta barrier in humans).
hCNT1 transporter: beyond nucleoside uptake
The therapeutic effects of many nucleoside-derived drugs are determined by the expression of these transporters on altered or infected cells. The research, centred on hCNT1 transporter expression, is based on the study of models of human pancreatic adenocarcinoma in mice developed by the expert Sandra Pérez Torras. The research carried out by the UB team proves that tumour growth is inhibited when hCNT1 is present and, surprisingly, it does not depend on drug administration to neoplastic cells.
hCNT1 transporter fits the profile of a transceptor —with dual activity— which plays a major role in tumour biology and development. "In other words—, besides its original nucleoside and nucleoside-derived drug transport function, it may establish a series of protein interactions that may affect cancer cell proliferation and migration", explains Pastor Anglada, who also heads the CIBERehd group on Transport Systems Regulation. The expert affirms that "these effects are also observed when the restoration of the expression of a mutated hCNT1, a protein that has lost its nucleoside transport ability, takes place".
Designing new strategies to fight against cancer
Many cancer cells may be perfectly able to proliferate when transporters are absent. This novel and totally unexpected biological role for the protein hCNT1, which appears to be independent of its role as a mediator of nucleoside uptake by cells, indicates that the problem does not appear when a drug gateway disappears. In short, if hCNT1 is expressed on cancer cells, a series of tumour phenotypic properties will be determined, independently of its role in drug transport. Other hCNT transporters may also have this dual biological activity. To develop new structural models of nucleoside transporters, to foster genomics research lines with animal models, and to identify nucleoside transporter structural and functional differences between prokaryotes and eukaryotes cells are some of the future objectives of this international research area which finally aims at designing new therapeutic strategies to inhibit cancer cells development and proliferation.
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