Gianni M, Terao M, Kurosaki M, Paroni G, Brunelli L, Pastorelli R, Zanetti A, Lupi M, Acquavita A, Bolis M, Fratelli M, Rochette-Egly C, Garattini E

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 ...

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

Date: Dec. 01, 2018

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