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 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.

Sulfopin, a selective covalent inhibitor of Pin1, blocks Myc-driven tumor initiation and growthin vivo

“…Furthermore, the sulfonyl oxygens mediate hydrogen bonds to the backbone amide of Gln131, and the imidazole NH of His157. These hydrogen bonds are analogous to those formed between Pin1 and arsenic trioxide 38 (Supp. Fig.…”

“…Indeed, compounds that inhibit Pin1, such as juglone 36 , all-trans retinoic acid (ATRA) 37 , arsenic trioxide (ATO) 38 and KPT-6566 39 , exhibit anti-cancer activity and have been used to investigate the role of Pin1 in oncogenesis. Nevertheless, these compounds have been shown to lack specificity and/or cell permeability thus making them unreliable as tools to interrogate the consequences of pharmacological inhibition of Pin1 in vivo [40][41][42] .…”

Predictive Value of Pin1 in Cervical Low-Grade Squamous Intraepithelial Lesions and Inhibition of Pin1 Exerts Potent Anticancer Activity against Human Cervical Cancer

“…Several studies have shown that Pin1 can activate multiple cancer-promoting pathways in human cancers [54]. Several Pin1 inhibitors have been identified to date, such as juglone, PiB and ATRA; these inhibitors have both covalent and non-covalent mechanisms of action [19].…”

Targeting PIN1 as a Therapeutic Approach for Hepatocellular Carcinoma

“…Most of the PIN1 inhibitors are non-covalent PIN1 inhibitors (e.g., PiB, ATRA, ATO, and API-1). Similar to covalent PIN1 inhibitor, non-covalent PIN1 inhibitor also directly binds to the PIN1 PPIase domain, but inhibits PIN1 activity in a competitive manner (Uchida et al, 2003;Wei et al, 2015;Kozono et al, 2018;Pu et al, 2018). However, there are limitations of these PIN1 inhibitors that restrict their clinical application ( Table 3).…”

“…The anti-cancer effect of ATO mainly depends on its ability to induce ubiquitin-dependent proteasomal degradation of various oncogenic proteins, including promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) in APL, cyclin D1 in mantle cell lymphoma, and nucleophosminanaplastic lymphoma kinase (NPM-ALK) in anaplastic large cell lymphoma (Shao et al, 1998;Lo and Kwong, 2014;Piao et al, 2017). Through the proteasome pathway, ATO has also been found to induce PIN1 degradation by directly binding to the PIN1 PPIase domain (Kozono et al, 2018). ATO-induced PIN1 degradation results in the suppression of multiple PIN1mediated oncogenic pathways and inhibition of breast cancer cell proliferation in vitro and in vivo.…”