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.