S100A3 a partner protein regulating the stability/activity of RARα and PML-RARα in cellular models of breast/lung cancer and acute myeloid leukemia

Maurizio Gianni, Mineko Terao, Mami Kurosaki, Gabriela Paroni, Laura Brunelli, Roberta Pastorelli, Adriana Zanetti, Monica Lupi, Andrea Acquavita, Marco Bolis, Maddalena Fratelli, Cecile Rochette-Egly, Enrico Garattini

Research output: Contribution to journalArticle

Abstract

All trans-retinoic acid (ATRA) is used in the treatment of acute promyelocytic leukemia (APL) and it is a promising agent also in solid tumors. The pharmacological activity of ATRA is mediated by the ligand-activated RAR and RXR transcription factors. In the present study, we define the basal and ATRA dependent RARα interactome in a RARα-overexpressing breast cancer cellular model, identifying 28 nuclear proteins. We focus our attention on the S100A3 calcium-binding protein, which interacts with RARα constitutively. In ATRA-sensitive breast cancer cells, S100A3 binds to RARα in basal conditions and binding is reduced by the retinoid. The interaction of S100A3 with RARα is direct and in lung cancer, APL and acute-myeloid-leukemia (AML) cells. In APL, S100A3 interacts not only with RARα, but also with PML-RARα. The interaction surface maps to the RARα ligand-binding domain, where the I396 residue plays a crucial role. Binding of S100A3 to RARα/PML-RARα controls the constitutive and ATRA-dependent degradation of these receptors. S100A3 knockdown decreases the amounts of RARα in breast- and lung cancer cells, inducing resistance to ATRA-dependent anti-proliferative/differentiating effects. Conversely, S100A3 knockdown in PML-RARα+ APL and PML-RARα- AML cells reduces the amounts of RARα/PML-RARα and increases basal and ATRA-induced differentiation. In this cellular context, opposite effects on RARα/PML-RARα levels and ATRA-induced differentiation are observed upon S100A3 overexpression. Our results provide new insights into the molecular mechanisms controlling RARα activity and have practical implications, as S100A3 represents a novel target for rational drug combinations aimed at potentiating the activity of ATRA.

Original languageEnglish
Pages (from-to)2482-2500
Number of pages19
JournalOncogene
Volume38
Issue number14
DOIs
Publication statusPublished - Apr 2019

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Keywords

  • A549 Cells
  • Animals
  • Breast Neoplasms/metabolism
  • COS Cells
  • Cell Differentiation/physiology
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation/physiology
  • Chlorocebus aethiops
  • Female
  • Humans
  • Leukemia, Promyelocytic, Acute/metabolism
  • Lung Neoplasms/metabolism
  • Promyelocytic Leukemia Protein/metabolism
  • Receptors, Retinoic Acid/metabolism
  • Retinoic Acid Receptor alpha/metabolism
  • S100 Proteins/metabolism

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