Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells
Open Access
- 9 August 2018
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 9 (1), 1-17
- https://doi.org/10.1038/s41467-018-05402-2
Abstract
Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but their mechanisms of action and efficacy are not fully understood. ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, like Pin1 knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic targeting of Pin1 by ATO and ATRA offers an attractive approach to combating breast and other cancers.Keywords
Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (R01CA167677, R01CA205153)
This publication has 83 references indexed in Scilit:
- Arsenic Binding to ProteinsChemical Reviews, 2013
- Proline Isomer-Specific Antibodies Reveal the Early Pathogenic Tau Conformation in Alzheimer's DiseaseCell, 2012
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Retinoic acid regulates bone morphogenic protein signal duration by promoting the degradation of phosphorylated Smad1Proceedings of the National Academy of Sciences of the United States of America, 2010
- Peptidyl-prolyl cis/trans isomerase Pin1 is critical for the regulation of PKB/Akt stability and activation phosphorylationOncogene, 2009
- Principles of Cancer Therapy: Oncogene and Non-oncogene AddictionCell, 2009
- The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem CellsCell, 2008
- Mechanisms of specificity in protein phosphorylationNature Reviews Molecular Cell Biology, 2007
- MicroRNA expression profiles classify human cancersNature, 2005
- Tumour stem cells and drug resistanceNature Reviews Cancer, 2005