Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer.

Autor:	Wei S; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [3] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA., Kozono S; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [3] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA., Kats L; 1] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [2] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, BIDMC, Harvard Medical School, Boston, Massachusetts, USA., Nechama M; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [3] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA., Li W; Department of Molecular Biosciences, University of Texas, Austin, Texas, USA., Guarnerio J; 1] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [2] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, BIDMC, Harvard Medical School, Boston, Massachusetts, USA., Luo M; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [3] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA., You MH; Division of Gerontology, Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA., Yao Y; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [3] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA., Kondo A; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [3] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA., Hu H; 1] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [2] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA., Bozkurt G; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Moerke NJ; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA., Cao S; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Reschke M; 1] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [2] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, BIDMC, Harvard Medical School, Boston, Massachusetts, USA., Chen CH; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [3] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA., Rego EM; Department of Internal Medicine, University of São Paulo, Ribeirão Preto, Brazil., Lo-Coco F; Department of Biomedicine and Prevention, Tor Vergata University and Santa Lucia Foundation, Rome, Italy., Cantley LC; 1] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [2] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA., Lee TH; Division of Gerontology, Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA., Wu H; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA., Zhang Y; Department of Molecular Biosciences, University of Texas, Austin, Texas, USA., Pandolfi PP; 1] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [2] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, BIDMC, Harvard Medical School, Boston, Massachusetts, USA., Zhou XZ; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [3] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA., Lu KP; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.. [3] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Nature medicine [Nat Med] 2015 May; Vol. 21 (5), pp. 457-66. Date of Electronic Publication: 2015 Apr 13.
DOI:	10.1038/nm.3839
Abstrakt:	A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.
Databáze:	MEDLINE
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