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National Institute of Environmental Health Sciences

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Publication Detail

Title: Elevated Hexokinase II Expression Confers Acquired Resistance to 4-Hydroxytamoxifen in Breast Cancer Cells.

Authors: Liu, Xiaochuan; Miao, Weili; Huang, Ming; Li, Lin; Dai, Xiaoxia; Wang, Yinsheng

Published In Mol Cell Proteomics, (2019 Nov)

Abstract: Tamoxifen has been clinically used in treating estrogen receptor (ER)-positive breast cancer for over 30 years. The most challenging aspect associated with tamoxifen therapy is the development of resistance in initially responsive breast tumors. We applied a parallel-reaction monitoring (PRM)-based quantitative proteomic method to examine the differential expression of kinase proteins in MCF-7 and the isogenic tamoxifen-resistant (TamR) cells. We were able to quantify the relative protein expression levels of 315 kinases, among which hexokinase 2 (HK2) and mTOR were up-regulated in TamR MCF-7 cells. We also observed that the TamR MCF-7 cells exhibited elevated rate of glycolysis than the parental MCF-7 cells. In addition, we found that phosphorylation of S6K - a target of mTOR - was much lower in TamR MCF-7 cells, and this phosphorylation level could be restored upon genetic depletion or pharmacological inhibition of HK2. Reciprocally, the level of S6K phosphorylation was diminished upon overexpression of HK2 in MCF-7 cells. Moreover, we observed that HK2 interacts with mTOR, and this interaction inhibits mTOR activity. Lower mTOR activity led to augmented autophagy, which conferred resistance of MCF-7 cells toward tamoxifen. Together, our study demonstrates that elevated expression of HK2 promotes autophagy through inhibiting the mTOR-S6K signaling pathway and results in resistance of MCF-7 breast cancer cells toward tamoxifen; thus, our results uncovered, for the first time, HK2 as a potential therapeutic target for overcoming tamoxifen resistance.

PubMed ID: 31519767 Exiting the NIEHS site

MeSH Terms: Antineoplastic Agents, Hormonal/pharmacology; Breast Neoplasms/drug therapy; Breast Neoplasms/metabolism; Breast Neoplasms/pathology*; Cell Proliferation; Drug Resistance, Neoplasm*; Female; Gene Expression Regulation, Neoplastic; Glycolysis; Hexokinase/metabolism*; Humans; MCF-7 Cells; Phosphorylation; Prognosis; Proteome/analysis*; Survival Rate; TOR Serine-Threonine Kinases/metabolism*; Tamoxifen/pharmacology*

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