期刊
HORMONES & CANCER
卷 9, 期 6, 页码 371-382出版社
SPRINGER
DOI: 10.1007/s12672-018-0343-8
关键词
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资金
- Komen for the Cure [SAC110039]
- Mayo Clinic SPORE in Breast Cancer [NIH/NCI P50CA116201-06A1]
- NIH/NCI Cancer Center Support Grant [2P30-CA077598]
- NATIONAL CANCER INSTITUTE [P50CA116201, P30CA077598] Funding Source: NIH RePORTER
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--positive (ER+) breast cancer cells (MCF-7 and T47D), NT157 also resulted in cytoplasmic ER downregulation likely because of disruption of an IRS-1-IGF-IR/InR/ER complex. NT157 decreased S phase fraction, monolayer, and anchorage-independent growth after IGF/insulin treatment in ER+ breast cancer cells. NT157 downregulation of IRS protein expression also sensitized ER+ breast cancer cells to rapamycin. Moreover, NT157 inhibited the growth of tamoxifen-resistant ER+ 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.
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