Thioridazine induces increase in expression of the pyruvate transporter MPC1 associated with immune infiltration in malignant tumors

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Abstract

The MPC1 gene is involved in the transport of pyruvate into mitochondria, playing an important role in metabolic processes. Recently, it has been reported that higher MPC1 expression correlates with an increased number of immune cells in human cervical and lung cancers, indicating an enhanced antitumor immune response. Reduced MPC1 levels in gastric tumors are associated with a more severe disease course. Correlational analysis of the MPC1 gene in human lung, hippocampus and frontal cortex tissue samples based on data from the GTEx database revealed associations of this gene with schizophrenia, non-small cell lung cancer, and immune diseases. Our experiments showed that the mRNA level of the MPC1 gene in the non-small cell lung cancer cell line A549 increases 5-fold under the influence of the schizophrenia neuroleptic thioridazine. The observed elevation of MPC1 level may cause tumor infiltration by immune cells, complementing the previously reported data indicating the ability of thioridazine to slow cell growth, induce apoptosis and reduce the ability of cells to migrate.

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About the authors

E. A. Bogomolova

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Author for correspondence.
Email: elvina.elochka@gmail.com

Laboratory of Intracellular Signaling in Health and Disease

Russian Federation, Moscow

M. M. Murashko

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Moscow Institute of Physics and Technology

Email: elvina.elochka@gmail.com

Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Department of Molecular and Biological Physics, Moscow Institute of Physics and Technology

Russian Federation, Moscow; Moscow

E. M. Stasevich

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Moscow Institute of Physics and Technology

Email: elvina.elochka@gmail.com

Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Department of Molecular and Biological Physics, Moscow Institute of Physics and Technology

Russian Federation, Moscow; Moscow

A. N. Uvarova

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: elvina.elochka@gmail.com

Laboratory of Intracellular Signaling in Health and Disease; Center for Precision Genome Editing and Genetic Technologies for Biomedicine

Russian Federation, Moscow

E. A. Zheremyan

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: elvina.elochka@gmail.com

Laboratory of Intracellular Signaling in Health and Disease; Center for Precision Genome Editing and Genetic Technologies for Biomedicine

Russian Federation, Moscow

K. V. Korneev

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: elvina.elochka@gmail.com

Laboratory of Intracellular Signaling in Health and Disease; Center for Precision Genome Editing and Genetic Technologies for Biomedicine

Russian Federation, Moscow

D. V. Kuprash

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: elvina.elochka@gmail.com

Laboratory of Intracellular Signaling in Health and Disease; Center for Precision Genome Editing and Genetic Technologies for Biomedicine; Corresponding Member of the RAS

Russian Federation, Moscow

D. E. Demin

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: denisdeminbio@gmail.com

Laboratory of Intracellular Signaling in Health and Disease; Center for Precision Genome Editing and Genetic Technologies for Biomedicine; Corresponding Member of the RAS

Russian Federation, Moscow

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2. Fig. 1. Genes correlating with MPC1 in lung tissues enrich functional groups associated with metabolic processes (A), immunopathologies (B), and lung cancer (C). The figure shows gene groups obtained as a result of correlation analysis of MPC1 mRNA expression in human lung tissue samples. (A) The strongest enrichments of functional groups obtained using the Metascape service. Enrichment of gene groups from the DisGeNet database associated with immune diseases (B) and lung cancer (C).

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3. Fig. 2. Effect of thioridazine on MPC1 mRNA expression. Expression levels measured by qPCR at different thioridazine concentrations. * denotes p-value less than 0.05 by Wilcoxon one-sample test.

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