Role of thyroid hormone-integrin αvβ3-signal and therapeutic strategies in colorectal cancers

• Main Authors: Yu-Chen S. H. Yang, Po-Jui Ko, Yi-Shin Pan, Hung-Yun Lin, Jacqueline Whang-Peng, Paul J. Davis, Kuan Wang
• Format: Article
• Language: English
• Published: BMC 2021-04-01
• Series: Journal of Biomedical Science
• Subjects: NDAT; Colorectal Cancer; Integrin αvβ3; Epidermal growth factor receptor; Ras mutation
• Online Access: https://doi.org/10.1186/s12929-021-00719-5

Abstract Thyroid hormone analogues—particularly, l-thyroxine (T4) has been shown to be relevant to the functions of a variety of cancers. Integrin αvβ3 is a plasma membrane structural protein linked to signal transduction pathways that are critical to cancer cell proliferation and metastasis. Thyroid hormones, T4 and to a less extend T3 bind cell surface integrin αvβ3, to stimulate the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway to stimulate cancer cell growth. Thyroid hormone analogues also engage in crosstalk with the epidermal growth factor receptor (EGFR)-Ras pathway. EGFR signal generation and, downstream, transduction of Ras/Raf pathway signals contribute importantly to tumor cell progression. Mutated Ras oncogenes contribute to chemoresistance in colorectal carcinoma (CRC); chemoresistance may depend in part on the activity of ERK1/2 pathway. In this review, we evaluate the contribution of thyroxine interacting with integrin αvβ3 and crosstalking with EGFR/Ras signaling pathway non-genomically in CRC proliferation. Tetraiodothyroacetic acid (tetrac), the deaminated analogue of T4, and its nano-derivative, NDAT, have anticancer functions, with effectiveness against CRC and other tumors. In Ras-mutant CRC cells, tetrac derivatives may overcome chemoresistance to other drugs via actions initiated at integrin αvβ3 and involving, downstream, the EGFR-Ras signaling pathways.