Cargando…

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

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. Using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocy...

Descripción completa

Detalles Bibliográficos
Autores principales: Wei, Shuo, Kozono, Shingo, Kats, Lev, Nechama, Morris, Li, Wenzong, Guarnerio, Jlenia, Luo, Manli, You, Mi-Hyeon, Yao, Yandan, Kondo, Asami, Hu, Hai, Bozkurt, Gunes, Moerke, Nathan J., Cao, Shugeng, Reschke, Markus, Chen, Chun-Hau, Rego, Eduardo M., LoCoco, Francesco, Cantley, Lewis, Lee, Tae Ho, Wu, Hao, Zhang, Yan, Pandolfi, Pier Paolo, Zhou, Xiao Zhen, Lu, Kun Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425616/
https://www.ncbi.nlm.nih.gov/pubmed/25849135
http://dx.doi.org/10.1038/nm.3839
_version_ 1782370509719076864
author Wei, Shuo
Kozono, Shingo
Kats, Lev
Nechama, Morris
Li, Wenzong
Guarnerio, Jlenia
Luo, Manli
You, Mi-Hyeon
Yao, Yandan
Kondo, Asami
Hu, Hai
Bozkurt, Gunes
Moerke, Nathan J.
Cao, Shugeng
Reschke, Markus
Chen, Chun-Hau
Rego, Eduardo M.
LoCoco, Francesco
Cantley, Lewis
Lee, Tae Ho
Wu, Hao
Zhang, Yan
Pandolfi, Pier Paolo
Zhou, Xiao Zhen
Lu, Kun Ping
author_facet Wei, Shuo
Kozono, Shingo
Kats, Lev
Nechama, Morris
Li, Wenzong
Guarnerio, Jlenia
Luo, Manli
You, Mi-Hyeon
Yao, Yandan
Kondo, Asami
Hu, Hai
Bozkurt, Gunes
Moerke, Nathan J.
Cao, Shugeng
Reschke, Markus
Chen, Chun-Hau
Rego, Eduardo M.
LoCoco, Francesco
Cantley, Lewis
Lee, Tae Ho
Wu, Hao
Zhang, Yan
Pandolfi, Pier Paolo
Zhou, Xiao Zhen
Lu, Kun Ping
author_sort Wei, Shuo
collection PubMed
description 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. 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 its 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 fusion oncogene PML-RARα and treats APL in cell and animal models and human patients. ATRA-induced Pin1 ablation also 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.
format Online
Article
Text
id pubmed-4425616
institution National Center for Biotechnology Information
language English
publishDate 2015
record_format MEDLINE/PubMed
spelling pubmed-44256162015-11-01 Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer Wei, Shuo Kozono, Shingo Kats, Lev Nechama, Morris Li, Wenzong Guarnerio, Jlenia Luo, Manli You, Mi-Hyeon Yao, Yandan Kondo, Asami Hu, Hai Bozkurt, Gunes Moerke, Nathan J. Cao, Shugeng Reschke, Markus Chen, Chun-Hau Rego, Eduardo M. LoCoco, Francesco Cantley, Lewis Lee, Tae Ho Wu, Hao Zhang, Yan Pandolfi, Pier Paolo Zhou, Xiao Zhen Lu, Kun Ping Nat Med Article 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. 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 its 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 fusion oncogene PML-RARα and treats APL in cell and animal models and human patients. ATRA-induced Pin1 ablation also 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. 2015-04-13 2015-05 /pmc/articles/PMC4425616/ /pubmed/25849135 http://dx.doi.org/10.1038/nm.3839 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wei, Shuo
Kozono, Shingo
Kats, Lev
Nechama, Morris
Li, Wenzong
Guarnerio, Jlenia
Luo, Manli
You, Mi-Hyeon
Yao, Yandan
Kondo, Asami
Hu, Hai
Bozkurt, Gunes
Moerke, Nathan J.
Cao, Shugeng
Reschke, Markus
Chen, Chun-Hau
Rego, Eduardo M.
LoCoco, Francesco
Cantley, Lewis
Lee, Tae Ho
Wu, Hao
Zhang, Yan
Pandolfi, Pier Paolo
Zhou, Xiao Zhen
Lu, Kun Ping
Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer
title Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer
title_full Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer
title_fullStr Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer
title_full_unstemmed Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer
title_short Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer
title_sort active pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425616/
https://www.ncbi.nlm.nih.gov/pubmed/25849135
http://dx.doi.org/10.1038/nm.3839
work_keys_str_mv AT weishuo activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT kozonoshingo activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT katslev activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT nechamamorris activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT liwenzong activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT guarneriojlenia activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT luomanli activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT youmihyeon activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT yaoyandan activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT kondoasami activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT huhai activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT bozkurtgunes activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT moerkenathanj activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT caoshugeng activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT reschkemarkus activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT chenchunhau activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT regoeduardom activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT lococofrancesco activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT cantleylewis activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT leetaeho activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT wuhao activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT zhangyan activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT pandolfipierpaolo activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT zhouxiaozhen activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer
AT lukunping activepin1isakeytargetofalltransretinoicacidinacutepromyelocyticleukemiaandbreastcancer