title: Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer.
abstract: 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.
authors: 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.
authors: Shuo
authors: S
authors: Wei
authors: 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.
authors: Shingo
authors: S
authors: Kozono
authors: 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.
authors: Lev
authors: L
authors: Kats
authors: 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.
authors: Morris
authors: M
authors: Nechama
authors: Department of Molecular Biosciences, University of Texas, Austin, Texas, USA.
authors: Wenzong
authors: W
authors: Li
authors: 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.
authors: Jlenia
authors: J
authors: Guarnerio
authors: 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.
authors: Manli
authors: M
authors: Luo
authors: Division of Gerontology, Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.
authors: Mi-Hyeon
authors: MH
authors: You
authors: 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.
authors: Yandan
authors: Y
authors: Yao
authors: 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.
authors: Asami
authors: A
authors: Kondo
authors: 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.
authors: Hai
authors: H
authors: Hu
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Gunes
authors: G
authors: Bozkurt
authors: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Nathan J
authors: NJ
authors: Moerke
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Shugeng
authors: S
authors: Cao
authors: 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.
authors: Markus
authors: M
authors: Reschke
authors: 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.
authors: Chun-Hau
authors: CH
authors: Chen
authors: Department of Internal Medicine, University of São Paulo, Ribeirão Preto, Brazil.
authors: Eduardo M
authors: EM
authors: Rego
authors: Department of Biomedicine and Prevention, Tor Vergata University and Santa Lucia Foundation, Rome, Italy.
authors: Francesco
authors: F
authors: Lo-Coco
authors: 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.
authors: Lewis C
authors: LC
authors: Cantley
authors: Division of Gerontology, Department of Medicine, BIDMC, Harvard Medical School, Boston, Massachusetts, USA.
authors: Tae Ho
authors: TH
authors: Lee
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Hao
authors: H
authors: Wu
authors: Department of Molecular Biosciences, University of Texas, Austin, Texas, USA.
authors: Yan
authors: Y
authors: Zhang
authors: 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.
authors: Pier Paolo
authors: PP
authors: Pandolfi
authors: 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.
authors: Xiao Zhen
authors: XZ
authors: Zhou
authors: 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.
authors: Kun Ping
authors: KP
authors: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009368:Neoplasm Transplantation; D019696:Peptidylprolyl Isomerase / Q000235:genetics*; D010710:Phosphates / Q000737:chemistry; D010766:Phosphorylation; D011392:Proline / Q000737:chemistry; D014212:Tretinoin / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010710:Phosphates; D014212:Tretinoin; D011392:Proline; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse