Paul J. Davis
Respiration in normal, nonmalignant cells is primarily regulated by 3,5,3’-triiodo-L-thyronine (T3), which acts on mitochondria and at nuclear receptors for thyroid hormone (TRs). Chemical modifications of tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T4), have been shown in cancer cells to have actions initiated at a plasma membrane receptor on the head of the extracellular domain of integrin αvβ3. These actions include inhibition of cell proliferation and cancer-linked angiogenesis that are the result of αvβ3-generated signals transduced into specific gene transcription. In the present report, we investigated whether the thyroid hormone analogue receptor on αvβ3 regulates expression of genes relevant to tumor cell respiration. The molecular probe for these studies was P-bi-TAT, an anticancer agent which consists of two tetrac molecules covalently bound separately via triazoles to a molecule of polyethylene glycol (PEG). P-bi-TAT has been shown in prior studies to be effective against glioblastoma (GBM) and other cancer cells and xenografts. . Microarray analysis was carried out on human GBM cells exposed to P-bi-TAT (10-6 M tetrac equivalent) for 24 h. P-bi-TAT significantly downregulated electron transport chain genes ATP5A1 (ATP synthase A1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase [ubiquinone] FA8), NDUFV2 and other NDUF genes, SLC25A6 (solute carrier group 2), UCP2 ([mitochondrial] uncoupling protein 2) and COX5A. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Six additional NDUF genes linked to oxidative phosphorylation were affected. Conclusions. P-bi-TAT caused downregulation of expression of a panel of genes involved in electron transport, oxidative phosphorylation, and cytoplasmic ribosomal protein generation in GBM cells. The actions were initiated at a cell surface thyroid hormone analogue receptor and are independent of TRs. A key component of the anticancer activity of P-bi-TAT relates to disordering of ATP generation mechanisms in tumor cells.
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