Cell & Stem Cell Research

Biography

Biography: Paul J Davis

Abstract

Integrin α_Vβ₃ is a structural protein of the plasma membrane that is generously expressed by cancer cells and dividing endothelial cells; until recently, important functions of the integrin have been seen to relate to cell-cell and cell-extracellular matrix protein interactions. The extracellular domain of αvβ₃ is now appreciated to contain a small molecule receptor for thyroid hormone, primarily, L-thyroxine (T4). From this cell surface hormone receptor, the expression of a large panel of cancer-relevant genes is differentially regulated by thyroid hormone analogues. These genes include multiple cell division regulating cyclins and HRAS and KRAS genes linked to uncontrolled cell division; KRAS is also related to cancer stem cell (CSC) maintenance and to tumor recurrence. Transcription of these genes is downregulated by P-bi-TAT, consisting of a thyroid hormone analogue, tetraiodothyroacetic acid (tetrac), chemically coupled to polyethylene glycol (PEG). IDH2 is involved in tumor cell mitochondrial metabolism; P-bi-TAT decreases IDH2 transcription, thus promoting apoptosis by the intrinsic (mitochondrial) pathway. Expression of ERBB2 is important to tumor cell invasiveness and metastasis and is downregulated by P-bi-TAT. The ERBB family of proteins is also important to tumor cell chemoresistance. αvβ3 regulates via the thyroid hormone receptor the transcription of ABCB1, whose gene product—the P-glycoprotein of the plasma membrane—exports a number of chemotherapeutic agents from tumor cells as a component of chemoresistance. Expression of pro-angiogenic VEGFA, bFGF and PDGF genes is also decreased by P-bi-TAT action at αvβ₃, as is the EGFR gene whose transcription is important to angiogenesis and tumor cell proliferation. Matrix metalloproteinase (MMP) gene expression is critical to cell migration/metastasis and to angiogenesis; P-bi-TAT induces a signal at the integrin to reduce MMP production. The EGFR protein is a tyrosine kinase and thus P-bi-TAT, by downregulating expression of EGFR, functions as a tumor cell-relevant tyrosine kinase inhibitor (TKI). Another TKI gene affected by P-bi-TAT is KIT. This complex set of actions of P-bi-TAT on gene expression implies that T4 may act on tumor cell αvβ₃ to support, rather than inhibit, the expression of these genes whose products are linked to tumor cell survival. We have shown that T4 via αvβ3 does stimulate expression of VEGFA and bFGF, of MMPs, ABCB1 in tumor cells. Transduction of thyroid hormone and hormone analogue signals downstream of αvβ₃ is a function of MAPK/ERK1/2 and PI3K, the genes and enzyme activities of which are regulated by thyroid hormone. These observations indicate that the importance of αvβ₃ to cancer cell function and survival also includes the actions of thyroid hormone analogues on the integrin.