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

Shingo Kozono, Yu-Min Lin, Hyuk-Soo Seo, Benika Pinch, Xiaolan Lian, Chenxi Qiu, Megan K. Herbert, Chun-Hau Chen, Li Tan, Ziang Jeff Gao, Walter Massefski, Zainab M. Doctor, Brian P. Jackson, Yuanzhong Chen, Sirano Dhe-Paganon, Kun Ping Lu () and Xiao Zhen Zhou ()
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Shingo Kozono: Harvard Medical School
Yu-Min Lin: Harvard Medical School
Hyuk-Soo Seo: Dana Farber Cancer Institute
Benika Pinch: Dana Farber Cancer Institute
Xiaolan Lian: Harvard Medical School
Chenxi Qiu: Harvard Medical School
Megan K. Herbert: Harvard Medical School
Chun-Hau Chen: Harvard Medical School
Li Tan: Dana Farber Cancer Institute
Ziang Jeff Gao: Harvard Medical School
Walter Massefski: Dana Farber Cancer Institute
Zainab M. Doctor: Dana Farber Cancer Institute
Brian P. Jackson: Dartmouth College
Yuanzhong Chen: Fujian Medical University
Sirano Dhe-Paganon: Dana Farber Cancer Institute
Kun Ping Lu: Harvard Medical School
Xiao Zhen Zhou: Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05402-2

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