Insulin Receptor Substrate Suppression by the Tyrphostin NT157 Inhibits Responses to Insulin-Like Growth Factor-I and Insulin in Breast Cancer Cells
| Autor: | Nuri A. Temiz, Yuzhe Yang, Jie Ying Chan, Douglas Yee |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Endocrinology Diabetes and Metabolism medicine.medical_treatment Antineoplastic Agents Breast Neoplasms Pyrogallol Article Metastasis 03 medical and health sciences Insulin-like growth factor 0302 clinical medicine Endocrinology Downregulation and upregulation Antigens CD Cell Movement Insulin receptor substrate Cell Line Tumor medicine Humans Insulin Insulin-Like Growth Factor I Receptor Cell Proliferation Sulfonamides biology Endocrine and Autonomic Systems Chemistry Estrogen Receptor alpha Tyrphostins medicine.disease Receptor Insulin IRS1 Insulin receptor 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Insulin Receptor Substrate Proteins Female Signal Transduction |
| Zdroj: | Hormonescancer. 9(6) |
| ISSN: | 1868-8500 |
| Popis: | Insulin and insulin-like growth factor (IGF) signaling systems regulate breast cancer growth, progression, and metastasis. The insulin receptor substrates 1 and 2 (IRS1/2) transduce signaling from the type I IGF receptor (IGF-IR) and insulin receptor (InR) to mediate the biological effects of receptor activation. In breast cancer, IRS-1 plays a critical role in cancer cell proliferation while IRS-2 is associated with motility and metastasis. NT157, a small-molecule tyrphostin, downregulates IRS proteins in several model systems. In breast cancer cells, NT157 treatment suppressed IRS protein expression in a dose-dependent manner. Exposure to NT157 inhibited the activation of downstream signaling mediated by the IRS proteins. NT157 induced a MAPK-dependent serine phosphorylation of IRS proteins which resulted in disassociation between IRS proteins and their receptors resulting in IRS degradation. In estrogen receptor-α-positive (ERα+) breast cancer cells (MCF-7 and T47D), NT157 also resulted in cytoplasmic ERα downregulation likely because of disruption of an IRS-1-IGF-IR/InR/ERα complex. NT157 decreased S phase fraction, monolayer, and anchorage-independent growth after IGF/insulin treatment in ERα+ breast cancer cells. NT157 downregulation of IRS protein expression also sensitized ERα+ breast cancer cells to rapamycin. Moreover, NT157 inhibited the growth of tamoxifen-resistant ERα+ breast cancer cells. Given that both IGF-IR and InR play a role in cancer biology, targeting of IRS adaptor proteins may be a more effective strategy to inhibit the function of these receptors. |
| Databáze: | OpenAIRE |
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