RSK-Mediated Non-canonical Activation of EphA2 by Tamoxifen

Biol Pharm Bull. 2022;45(2):162-168. doi: 10.1248/bpb.b21-00567.

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.

Keywords: EphA2; estrogen receptor; extracellular signal-regulated kinase (ERK); migration; ribosomal S6 kinase (RSK); tamoxifen.

MeSH terms

  • 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
  • Receptor, EphA2 / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Tamoxifen / pharmacology*

Substances

  • Antineoplastic Agents, Hormonal
  • EPHA2 protein, human
  • Estrogen Receptor alpha
  • Tamoxifen
  • Receptor, EphA2
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa