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Article

Effects of Anticancer Agent P-bi-TAT on Gene Expression Link the Integrin Thyroid Hormone Receptor to Expression of Stemness and Energy Metabolism Genes in Cancer Cells

1
Institute of Engineering in Medicine, University of California San Diego, San Diego, CA 92037, USA
2
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, One Discovery Drive, Rensselaer, NY 12144, USA
3
Center for Functional Genomics, University at Albany, Rensselaer, NY 12144, USA
4
Cleveland Clinic, Cleveland, OH 44195, USA
5
Department of Medicine, Albany Medical College, Albany, NY 12208, USA
*
Authors to whom correspondence should be addressed.
Academic Editors: Monica Dentice and Annunziata Gaetana Cicatiello
Metabolites 2022, 12(4), 325; https://doi.org/10.3390/metabo12040325
Received: 7 March 2022 / Revised: 1 April 2022 / Accepted: 1 April 2022 / Published: 4 April 2022
(This article belongs to the Special Issue Metabolic Effects of the Intracellular Regulation of Thyroid Hormone)
Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have been shown to exert their anticancer activity at plasma membrane integrin αvβ3 of tumor cells. Via a specific hormone receptor on the integrin, tetrac-based therapeutic agents modulate expression of genes relevant to cancer cell proliferation, survival and energy metabolism. P-bi-TAT, a novel bivalent tetrac-containing synthetic compound has anticancer activity in vitro and in vivo against glioblastoma multiforme (GBM) and other types of human cancers. In the current study, microarray analysis was carried out on a primary culture of human GBM cells exposed to P-bi-TAT (10−6 tetrac equivalent) for 24 h. P-bi-TAT significantly affected expression of a large panel of genes implicated in cancer cell stemness, growth, survival and angiogenesis. Recent interest elsewhere in ATP synthase as a target in GBM cells caused us to focus attention on expression of genes involved in energy metabolism. Significantly downregulated transcripts included multiple energy-metabolism-related genes: electron transport chain genes ATP5A1 (ATP synthase 1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase (ubiquinone) FA8), NDUFV2I and other NDUF genes. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Qualitatively similar actions of P-bi-TAT on expression of subsets of energy-metabolism-linked genes were also detected in established human GBM and pancreatic cancer cell lines. In conclusion, acting at αvβ3 integrin, P-bi-TAT caused downregulation in human cancer cells of expression of a large number of genes involved in electron transport and oxidative phosphorylation. These observations suggest that cell surface thyroid hormone receptors on αvβ3 regulate expression of genes relevant to tumor cell stemness and energy metabolism. View Full-Text
Keywords: ATP synthase; cancer cells; mitochondria; glioblastoma; integrin αvβ3; NADH dehydrogenase; tetrac; thyroid hormones ATP synthase; cancer cells; mitochondria; glioblastoma; integrin αvβ3; NADH dehydrogenase; tetrac; thyroid hormones
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MDPI and ACS Style

Glinsky, G.V.; Godugu, K.; Sudha, T.; Rajabi, M.; Chittur, S.V.; Hercbergs, A.A.; Mousa, S.A.; Davis, P.J. Effects of Anticancer Agent P-bi-TAT on Gene Expression Link the Integrin Thyroid Hormone Receptor to Expression of Stemness and Energy Metabolism Genes in Cancer Cells. Metabolites 2022, 12, 325. https://doi.org/10.3390/metabo12040325

AMA Style

Glinsky GV, Godugu K, Sudha T, Rajabi M, Chittur SV, Hercbergs AA, Mousa SA, Davis PJ. Effects of Anticancer Agent P-bi-TAT on Gene Expression Link the Integrin Thyroid Hormone Receptor to Expression of Stemness and Energy Metabolism Genes in Cancer Cells. Metabolites. 2022; 12(4):325. https://doi.org/10.3390/metabo12040325

Chicago/Turabian Style

Glinsky, Gennadi V., Kavitha Godugu, Thangirala Sudha, Mehdi Rajabi, Sridar V. Chittur, Aleck A. Hercbergs, Shaker A. Mousa, and Paul J. Davis. 2022. "Effects of Anticancer Agent P-bi-TAT on Gene Expression Link the Integrin Thyroid Hormone Receptor to Expression of Stemness and Energy Metabolism Genes in Cancer Cells" Metabolites 12, no. 4: 325. https://doi.org/10.3390/metabo12040325

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