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

Autor: Andrea Acquavita, Laura Brunelli, Adriana Zanetti, Roberta Pastorelli, Maurizio Gianni, Gabriela Paroni, Mineko Terao, Mami Kurosaki, Cécile Rochette-Egly, Enrico Garattini, Maddalena Fratelli, Marco Bolis, Monica Lupi
Přispěvatelé: univOAK, Archive ouverte, IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Acute promyelocytic leukemia
Proteomics
Cancer Research
Lung Neoplasms
Receptors
Retinoic Acid
Context (language use)
[SDV.CAN]Life Sciences [q-bio]/Cancer
Breast Neoplasms
Biology
Retinoid X receptor
Promyelocytic Leukemia Protein
Article
Acute myeloid leukaemia
Cell Line
03 medical and health sciences
0302 clinical medicine
[SDV.CAN] Life Sciences [q-bio]/Cancer
Leukemia
Promyelocytic
Acute
Cell Line
Tumor
Chlorocebus aethiops
Genetics
medicine
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Nuclear protein
Molecular Biology
Transcription factor
neoplasms
Cell Proliferation
A549 cell
Gene knockdown
Retinoic Acid Receptor alpha
organic chemicals
S100 Proteins
Myeloid leukemia
Cell Differentiation
medicine.disease
biological factors
030104 developmental biology
A549 Cells
030220 oncology & carcinogenesis
COS Cells
Cancer research
Female
Zdroj: Oncogene
Oncogene, 2019, 38 (14), pp.2482-2500. ⟨10.1038/s41388-018-0599-z⟩
ISSN: 1476-5594
0950-9232
Popis: 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.
Databáze: OpenAIRE
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