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

ABSTRACT: Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but the mechanisms underlying their action and synergy remain elusive. ATRA inhibits APL, breast and liver cancers by targeting isomerase Pin1, a master regulator of oncogenic signaling. 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, similar to Pin1 CRISPR knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic Pin1 inhibition by ATO and ATRA offers an attractive approach to combating breast and other cancers.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Cancer Cell Line

DISEASE(S): Breast Cancer

SUBMITTER: Chenxi Qiu  

LAB HEAD: Kun Ping Lu

PROVIDER: PXD010224 | Pride | 2018-10-16

REPOSITORIES: Pride