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

Autor:	Kozono S; Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Lin YM; Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Seo HS; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02115, USA., Pinch B; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02115, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA., Lian X; Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.; Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350108, China.; Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, 350108, China., Qiu C; Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Herbert MK; Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Chen CH; Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Tan L; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02115, USA., Gao ZJ; Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Massefski W; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02115, USA., Doctor ZM; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02115, USA., Jackson BP; Trace Element Analysis Lab, Dartmouth College, Hanover, NH, 03755, USA., Chen Y; Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou, Fujian, 350108, China., Dhe-Paganon S; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02115, USA., Lu KP; Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. klu@bidmc.harvard.edu.; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. klu@bidmc.harvard.edu.; 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.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. klu@bidmc.harvard.edu., Zhou XZ; Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. xzhou@bidmc.harvard.edu.; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. xzhou@bidmc.harvard.edu.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. xzhou@bidmc.harvard.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 Aug 09; Vol. 9 (1), pp. 3069. Date of Electronic Publication: 2018 Aug 09.
DOI:	10.1038/s41467-018-05402-2
Abstrakt:	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.
Databáze:	MEDLINE
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