Reduction of Progranulin-Induced Breast Cancer Stem Cell Propagation by Sortilin-Targeting Cyclotriazadisulfonamide (CADA) Compounds

Abstract

Cyclotriazadisulfonamide (CADA) compounds selectively down-modulate two human proteins of potential therapeutic interest, cluster of differentiation 4 (CD4) and sortilin. Progranulin is secreted from some breast cancer cells, causing dedifferentiation of receiving cancer cells and cancer stem cell proliferation. Inhibition of progranulin binding to sortilin, its main receptor, can block progranulin-induced metastatic breast cancer using a triple-negative in vivo xenograft model. In the current study, seven CADA compounds (CADA, VGD020, VGD071, TL020, TL023, LAL014, and DJ010) were examined for reduction of cellular sortilin expression and progranulin-induced breast cancer stem cell propagation. In addition, inhibition of progranulin-induced mammosphere formation was examined and found to be most significant for TL020, TL023, VGD071, and LAL014. Full experimental details are given for the synthesis and characterization of the four new compounds (TL020, TL023, VGD071, and DJ010). Comparison of solubilities, potencies, and cytotoxicities identified VGD071 as a promising candidate for future studies using mouse breast cancer models.

Progranulin Oncogenic Network in Solid Tumors

“…On the other hand, in breast cancer, progranulin action is mediated by sortilin, as, in fact, progranulin promoted breast cancer CSC’ expansion in a sortilin-dependent manner [ 84 ]. In agreement with a role for sortilin in supporting progranulin oncogenic action, sortilin inhibition counteracted progranulin-dependent breast cancer progression and CSC expansion [ 84 , 85 ]. Furthermore, co-expression of progranulin and sortilin might work as a biomarker, which identifies a highly malignant subgroup of breast cancers [ 115 ].…”

“…In addition, progranulin depletion reduced self-renewal and multilineage differentiation capacity of R1S1 glioblastoma cells, contributing to temozolomide resistance [ 83 ]. In breast cancer, progranulin promoted proliferation of CSC and caused their dedifferentiation in a sortilin-dependent manner, suggesting a critical role for progranulin and sortilin in the maintenance of breast CSC [ 84 , 85 ].…”

Inhibitors of the Sec61 Complex and Novel High Throughput Screening Strategies to Target the Protein Translocation Pathway

“…In addition to the reported CD4-mediated antiviral effect for CADA, recently, a CD8 + T-cell mediated immunosuppressive effect was described that is related to the CADA-induced suppression of CD137 upregulation [ 158 ]. Furthermore, partial downmodulation of the sortilin protein by CADA [ 159 ] has recently been linked to a reduction in progranulin-induced breast cancer stem cell propagation [ 163 ], thus, suggesting an additional anticancer effect for CADA.…”

“…The relatively small size of CADA stimulated the synthesis of numerous analogs that could be implemented in SAR studies [ 102 , 163 , 164 , 165 , 166 , 167 , 168 , 169 ]. These SAR studies were all based on the biological effect of CADA analogs on the cellular expression of the huCD4 receptor, and structure optimization resulted in improved activity going from µM to the nM range [ 165 ].…”

HSP90 facilitates stemness and enhances glycolysis in glioma cells

“…Cancer stem cells (CSCs) promote tumor development in head and neck cancer [10,11] [12], breast cancer [13], gastric cancer [14] and glioma. At the molecular level, miR-663a [15], the FOSL1-miR-27a-5p axis [16], and miR-504 regulate the stemness of Glioma CSCs, influencing both tumor progression and radiosensitivty [17].…”