Dataset Information

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

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 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.

SUBMITTER: Gianni M

PROVIDER: S-EPMC6484772 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Gianni Maurizio M Terao Mineko M Kurosaki Mami M Paroni Gabriela G Brunelli Laura L Pastorelli Roberta R Zanetti Adriana A Lupi Monica M Acquavita Andrea A Bolis Marco M Fratelli Maddalena M Rochette-Egly Cecile C Garattini Enrico E

Oncogene 20181207 14

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 ...[more]

PMID: 30532072

Similar Datasets

Project description:Although dyslipidemia commonly occurs in patients with acute promyelocytic leukemia (APL) in response to anti-APL therapy, the underlying mechanism and the lipid statuses of patients with newly diagnosed APL remain to be addressed. Methods: We conducted a retrospective study to investigate the lipid profiles of APL patients. PML-RARα transgenic mice and APL cells-transplanted mice were used to assess the effects of APL cells on the blood/liver lipid levels. Subsequently, gene set enrichment analysis, western blot and dual luciferase reporter assay were performed to examine the role and mechanism of PML-RARα and TRIB3 in lipid metabolism regulation in APL patients at pretreatment and after induction therapy. Results: APL patients exhibited a higher prevalence of dyslipidemia before anti-APL therapy based on a retrospective study. Furthermore, APL cells caused secretion of triglycerides, cholesterol, and PCSK9 from hepatocytes and degradation of low-density lipoprotein receptors in hepatocytes, which elevated the lipid levels in APL cell-transplanted mice and Pml-Rarα transgenic mice. Mechanistically, pseudokinase TRIB3 interacted with PML-RARα to inhibit PPARγ activity by interfering with the interaction of PPARγ and RXR and promoting PPARγ degradation. Thus, reduced PPARγ activity in APL cells decreased leptin but increased resistin expression, causing lipid metabolism disorder in hepatocytes and subsequent dyslipidemia in mice. Although arsenic/ATRA therapy degraded PML-RARα and restored PPARγ expression, it exacerbated dyslipidemia in APL patients. The elevated TRIB3 expression in response to arsenic/ATRA therapy suppressed PPARγ activity by disrupting the PPARγ/RXR dimer, which resulted in dyslipidemia in APL patients undergoing therapy. Indeed, the PPAR activator not only enhanced the anti-APL effects of arsenic/ATRA by suppressing TRIB3 expression but also reduced therapy-induced dyslipidemia in APL patients. Conclusion: Our work reveals the critical role of the PML-RARα/PPARγ/TRIB3 axis in the development of dyslipidemia in APL patients, potentially conferring a rationale for combining ATRA/arsenic with the PPAR activator for APL treatment.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets