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

Shuo Wei, Shingo Kozono, Lev Kats, Morris Nechama, Wenzong Li, Jlenia Guarnerio, Manli Luo, Mi Hyeon You, Yandan Yao, Asami Kondo, Hai Hu, Gunes Bozkurt, Nathan J. Moerke, Shugeng Cao, Markus Reschke, Chun Hau Chen, Eduardo M. Rego, Francesco Lo-Coco, Lewis C. Cantley, Tae Ho LeeHao Wu, Yan Zhang, Pier Paolo Pandolfi, Xiao Zhen Zhou, Kun Ping Lu

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)457-466
Number of pages10
JournalNature Medicine
Volume21
Issue number5
DOIs
Publication statusPublished - May 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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  • Cite this

    Wei, S., Kozono, S., Kats, L., Nechama, M., Li, W., Guarnerio, J., Luo, M., You, M. H., Yao, Y., Kondo, A., Hu, H., Bozkurt, G., Moerke, N. J., Cao, S., Reschke, M., Chen, C. H., Rego, E. M., Lo-Coco, F., Cantley, L. C., ... Lu, K. P. (2015). Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nature Medicine, 21(5), 457-466. https://doi.org/10.1038/nm.3839