Disulfiram/Copper Suppresses Cancer Stem Cell Activity in Differentiated Thyroid Cancer Cells by Inhibiting BMI1 Expression

Abstract

Differentiated thyroid carcinomas (DTCs), which have papillary and follicular types, are common endocrine malignancies worldwide. Cancer stem cells (CSCs) are a particular type of cancer cells within bulk tumors involved in cancer initiation, drug resistance, and metastasis. Cells with high intracellular aldehyde hydrogenase (ALDH) activity are a population of CSCs in DTCs. Disulfiram (DSF), an ALDH inhibitor used for the treatment of alcoholism, reportedly targets CSCs in various cancers when combined with copper. This study reported for the first time that DSF/copper can inhibit the proliferation of papillary and follicular DTC lines. DSF/copper suppressed thyrosphere formation, indicating the inhibition of CSC activity. Molecular mechanisms of DSF/copper involved downregulating the expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and cell cycle-related proteins, including cyclin B2, cyclin-dependent kinase (CDK) 2, and CDK4, in a dose-dependent manner. BMI1 overexpression diminished the inhibitory effect of DSF/copper in the thyrosphere formation of DTC cells. BMI1 knockdown by RNA interference in DTC cells also suppressed the self-renewal capability. DSF/copper could inhibit the nuclear localization and transcriptional activity of c-Myc and the binding of E2F1 to the BMI1 promoter. Overexpression of c-Myc or E2F1 further abolished the inhibitory effect of DSF/copper on BMI1 expression, suggesting that the suppression of c-Myc and E2F1 by DSF/copper was involved in the downregulation of BMI1 expression. In conclusion, DSF/copper targets CSCs in DTCs by inhibiting c-Myc- or E2F1-mediated BMI1 expression. Therefore, DSF is a potential therapeutic agent for future therapy in DTCs.

Polymer/copper nanocomplex-induced lysosomal cell death promotes tumor lymphocyte infiltration and synergizes anti-PD-L1 immunotherapy for triple-negative breast cancer

“…29,30 One of the main targets of the DSF/copper complex is the ubiquitin/proteasome system (UPS). 31 The ubiquitin/proteasome system is a highly regulated mechanism for intracellular protein degradation, which plays an essential role in many fundamental cellular activities. 32,33 A protein must be ubiquitinated before it can be transferred to the 26S proteasome system for degradation.…”

Potential of Copper and Copper Compounds for Anticancer Applications

“…Cells with high intracellular aldehyde hydrogenase (ALDH) activity are the population of CSCs in DTCs. Yung-Lun Ni et al found that DSF/copper can target the B lymphoma Mo-MLV insertion region 1 homolog (BMI1) by inhibiting c-Myc or the E2F1-mediated expression of CSCs in DTCs [ 96 ]. Therefore, DSF/copper is a potential therapeutic agent for the future treatment of DTCs.…”

Special Issue: “Drug Repurposing for Cancer Therapies”

“…In another approach, Yung-Lun Ni et al reported that disulfiram, an approved drug for the treatment of alcoholism, targeted cancer stem cells in thyroid carcinoma when combined with copper [8]. Indeed, the combination of disulfiram and copper not only hindered cell proliferation but also suppressed spheroid formation and inhibited the activity of cancer stem cells in multiple differentiated thyroid carcinoma cell lines.…”