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Nat Commun. 2018 Aug 9;9(1):3069. doi: 10.1038/s41467-018-05402-2.

Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells.

Kozono S1,2, Lin YM1,2, Seo HS3, Pinch B3,4, Lian X1,2,5,6, Qiu C1,2,7, Herbert MK1,2, Chen CH1,2, Tan L3, Gao ZJ1,2, Massefski W3, Doctor ZM3, Jackson BP8, Chen Y6, Dhe-Paganon S3, Lu KP9,10,11,12, Zhou XZ13,14,15.

Author information

1
Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
2
Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
3
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.
4
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
5
Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350108, China.
6
Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, 350108, China.
7
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
8
Trace Element Analysis Lab, Dartmouth College, Hanover, NH, 03755, USA.
9
Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. klu@bidmc.harvard.edu.
10
Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. klu@bidmc.harvard.edu.
11
Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, 350108, China. klu@bidmc.harvard.edu.
12
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. klu@bidmc.harvard.edu.
13
Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. xzhou@bidmc.harvard.edu.
14
Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. xzhou@bidmc.harvard.edu.
15
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. xzhou@bidmc.harvard.edu.

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.

PMID:
30093655
PMCID:
PMC6085299
DOI:
10.1038/s41467-018-05402-2
[Indexed for MEDLINE]
Free PMC Article

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