Human prostate epithelial cells and prostate-derived stem cells malignantly transformed in vitro with sodium arsenite show impaired Toll like receptor-3 (TLR3)-associated anti-tumor pathway

A therapeutic strategy for prostate cancer (PCa) involves the use of 9-cis-retinoic acid (9cRA) to induce cancer stem cells (CSCs) differentiation and apoptosis. Polyinosinic:polycytidylic acid (PIC) is a Toll-like receptor 3 (TLR3) agonist that induces tumor cells apoptosis after activation. PIC+9cRA combination activates retinoic acid receptor beta (RAR beta) re-expression. leading to CSC differentiation and growth arrest. Since inorganic arsenic (iAs) targets prostatic stem cells (SCs). we hypothesized that arsenic-transformed SCs (As-CSCs) show an impaired TLR3-associated anti-tumor pathway and, therefore. are unresponsive to PIC activation. We evaluated TLR3-mediated activation of anti-tumor pathway based in RAR beta expression, on As-CSC and iAs-transformed epithelial cells (CASE-PE). As-CSCs and CAsE-PE showed lower TLR3 and RAR beta basal expression compared to their respective isogenic controls WPE-Stem and RWPE-1. Also. iAs transformants showed reduced expression of mediators in TLR3 pathway. Importantly, As-CSCs were irresponsive to PIC+9cRA in terms of increased RAR beta and decreased SC-markers expression, while CAsE-PE, a heterogeneous cell line having a small SC population, were partially responsive. These observations indicate that iAs can impair TLR3 expression and anti-tumor pathway activated by PIC+9cRA in SCs and prostatic epithelial cells. These findings suggest that TLR3-activation based therapy may be an ineffective therapeutic alternative for iAs-associated PCa. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The study suggests that arsenic may impair the TLR3-associated anti-tumor pathway activated by 9cRA and PIC in prostate cancer stem cells and epithelial cells, leading to unresponsiveness to therapy.