RSK-Mediated Non-canonical Activation of EphA2 by Tamoxifen.

Abstract	The long-term administration of tamoxifen to estrogen receptor α (ERα)-positive breast cancer patients is an established treatment that reduces mortality and recurrence. However, resistance to tamoxifen and an increased risk of endometrial cancer may occur; therefore, the mechanisms by which tamoxifen causes these adverse effects warrant further study. Tamoxifen has been shown to activate mitogen-activated protein kinase (MAPK) in an ERα-independent manner; therefore, we investigated its effects on the MAPK-mediated non-canonical activation of EphA2, a critical event regulating cell migration. Tamoxifen at slightly higher concentrations induced the rapid phosphorylation of EphA2 at Ser-897 via the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK-ribosomal S6 kinases (RSK) pathway in HeLa cells. In addition, tamoxifen significantly enhanced the migration ability of ERα-negative MDA-MB-231 breast cancer cells in RSK- and EphA2-dependent manners. Phosphorylated EphA2 was internalized and re-localized to the plasma membrane, including lamellipodia, in an RSK-dependent manner. Collectively, the present results provide novel insights into the tumor-promoting activity of tamoxifen.
Authors	Keisuke Yonehara, Yue Zhou, Jun-Ichiro Takahashi, Satoru Yokoyama, Kei Tomihara, Makoto Noguchi, Hiroaki Sakurai
Journal	Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 45 Issue 2 Pg. 162-168 ( 2022) ISSN: 1347-5215 [Electronic] Japan
PMID	35110502 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents, Hormonal EPHA2 protein, human Estrogen Receptor alpha Tamoxifen Receptor, EphA2 RPS6KA1 protein, human Ribosomal Protein S6 Kinases, 90-kDa
Topics	Antineoplastic Agents, Hormonal (pharmacology) Breast Neoplasms (metabolism) Cell Line, Tumor Cell Movement Estrogen Receptor alpha Female Gene Expression Regulation, Neoplastic (drug effects) Humans Phosphorylation Receptor, EphA2 (genetics, metabolism) Ribosomal Protein S6 Kinases, 90-kDa (genetics, metabolism) Tamoxifen (pharmacology)

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