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

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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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E. Bogomolova

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

编辑信件的主要联系方式.
Email: elvina.elochka@gmail.com

Laboratory of Intracellular Signaling in Health and Disease

俄罗斯联邦, Moscow

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

俄罗斯联邦, Moscow; Moscow

E. 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

俄罗斯联邦, Moscow; Moscow

A. 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

俄罗斯联邦, Moscow

E. 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

俄罗斯联邦, Moscow

K. 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

俄罗斯联邦, Moscow

D. 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

俄罗斯联邦, Moscow

D. 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

俄罗斯联邦, Moscow

参考

  1. Minna J.D., Roth J.A., Gazdar A.F. Focus on lung cancer // Cancer Cell. 2002. 1(1). Р. 49–52.
  2. Saigi M., Alburquerque-Bejar J.J., Sanchez-Cespedes M. Determinants of immunological evasion and immunocheckpoint inhibition response in nonsmall cell lung cancer: the genetic front // Oncogene. 2019. 38(31). Р. 5921–5932.
  3. Li F., Huang C., Zhou M., et al. MPC1 is downregulated in lung cancer and associated with immune Infiltration // Piccaluga P.P., El-Hashash A., Guo X., eds. Fourth International Conference on Biomedicine and Bioinformatics Engineering (ICBBE 2024). SPIE. 2024:27.
  4. Li M., Xu T., Yang R., Wang X., Zhang J., Wu S. Exploring MPC1 as a potential ferroptosislinked biomarker in the cervical cancer tumor microenvironment: a comprehensive analysis // BMC Cancer. 2024. 24(1). Р. 1258.
  5. Zhou X., Xiong Z. juan, Xiao S. meng, et al. Overexpression of MPC1 inhibits the proliferation, migration, invasion, and stem cell-like properties of gastric cancer cells // OncoTargets Ther. 2017. 10. Р. 5151–5163.
  6. Yang Y., Wang L., Li L., et al. Genetic association and meta-analysis of a schizophrenia GWAS variant rs10489202 in East Asian populations // Transl Psychiatry. 2018. 8(1). Р. 1–11.
  7. Qian G., Dai L., Yu T. Thioridazine Sensitizes Cisplatin Against Chemoresistant Human Lung and Ovary Cancer Cells // DNA Cell Biol. 2019. 38(7). Р. 718–724.
  8. Baig M.S., Roy A., Saqib U., et al. Repurposing Thioridazine (TDZ) as an anti-inflammatory agent // Sci Rep. 2018. 8(1). Р. 12471.
  9. Shen J., Ma B., Zhang X., et al. Thioridazine has potent antitumor effects on lung cancer stem-like Cells // Oncol Lett. 2017. 13(3). Р. 1563–1568.
  10. Lianos G.D., Alexiou G.A., Rausei S., Galani V., Mitsis M., Kyritsis A.P. Repurposing antipsychotic drugs for cancer treatment: current evidence and future perspectives // Expert Rev Anticancer Ther. Published online February 1, 2022. Accessed October 25, 2024.
  11. Demin D.E., Murashko M.M., Uvarova A.N., et al. Adversary of DNA integrity: A long non-coding RNA stimulates driver oncogenic chromosomal rearrangement in human thyroid cells // Int J Cancer. 2023. 52(7). Р. 1452–1462.
  12. Demin D.E., Stasevich E.M., Murashko M.M., Tkachenko E.A., Uvarova A.N., Schwartz A.M. Full and D-Box-Deficient PTTG1 Isoforms: Effects on Cell Proliferation // Mol Biol (Mosk). 2022. 56(6). Р. 1104.
  13. Zou H., Yin Y., Xiong K., et al. Mitochondrial Pyruvate Carrier 1 as a Novel Prognostic Biomarker in Non-Small Cell Lung Cancer // Technol Cancer Res Treat. 2024. 23:15330338241282080.
  14. Zou H., Chen Q., Zhang A., et al. MPC1 deficiency accelerates lung adenocarcinoma progression through the STAT3 pathway // Cell Death Dis. 2019. 10(3). Р. 148.
  15. Huang W. Thioridazine promotes primary ciliogenesis in lung cancer cells through enhancing cell autophagy // Int J Clin Exp Med. 2017. 10. Р. 13960–13969.
  16. Mårtensson E., Roos B.E. Serum levels of thioridazine in psychiatric patients and healthy volunteers // Eur J Clin Pharmacol. 1973. 6(3). Р. 181–186.
  17. Cohen B.M., Lipinski J.F., Waternaux C. A fixed dose study of the plasma concentration and clinical effects of thioridazine and its major metabolites // Psychopharmacology (Berl). 1989. 97(4). Р. 481–488.
  18. Groothuis F.A., Heringa M.B., Nicol B., Hermens J.L.M., Blaauboer Bas J., Kramer N.I. Dose metric considerations in in vitro assays to improve quantitative in vitro-in vivo dose extrapolations // Toxicology. 2015. 332. Р. 30–40.
  19. Ma Q.Y., Huang D.Y., Zhang H.J., Chen J., Miller W., Chen X.F. Function of follicular helper T cell is impaired and correlates with survival time in nonsmall cell lung cancer // Int Immunopharmacol. 2016. 41. Р. 1–7.

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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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