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Arsenic; PIC; Poly (I:C); Prostate cancer; RARβ; Retinoic acid; TLR3 arsenite sodium; DNA (cytosine 5) methyltransferase 1; DNA methyltransferase 3A; messenger RNA; microRNA; microRNA 148b; microRNA 152; microRNA 29c; polyinosinic polycytidylic acid; retinoic acid receptor beta; toll like receptor 3; unclassified drug; sodium derivative; toll like receptor; apoptosis; Article; cancer growth; cancer stem cell; cell differentiation; comparative study; controlled study; human; human cell; human tissue; in vitro study; male; malignant transformation; mediator; mRNA expression level; prostate cancer; prostate epithelium cell; RNA extraction; RWPE-1 cell line; TLR signaling; adult; aged; cancer stem cell; cell culture; cell transformation; drug effect; epithelium cell; genetic variation; genetics; genotype; metabolism; middle aged; pathophysiology; prostate; prostate tumor; very elderly; Adult; Aged; Aged, 80 and over; Apoptosis; Cell Transformation, Neoplastic; Cells, Cultured; Epithelial Cells; Genetic Variation; Genotype; Humans; Male; Middle Aged; Neoplastic Stem Cells; Prostate; Prostatic Neoplasms; Sodium Compounds; Toll-Like Receptors
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 β (RARβ) 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 RARβ expression, on As-CSC and iAs-transformed epithelial cells (CAsE-PE). As-CSCs and CAsE-PE showed lower TLR3 and RARβ 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 RARβ 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. © 2021 Elsevier B.V.
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%2b9cRA combination activates retinoic acid receptor β (RARβ) 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 RARβ expression, on As-CSC and iAs-transformed epithelial cells (CAsE-PE). As-CSCs and CAsE-PE showed lower TLR3 and RARβ 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%2b9cRA in terms of increased RARβ 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%2b9cRA in SCs and prostatic epithelial cells. These findings suggest that TLR3-activation based therapy may be an ineffective therapeutic alternative for iAs-associated PCa. © 2021 Elsevier B.V.
arsenite sodium, 13464-37-4; DNA (cytosine 5) methyltransferase; DNA (cytosine 5) methyltransferase 1; polyinosinic polycytidylic acid, 24939-03-5, 26301-44-0; toll like receptor, 409141-78-2; Sodium Compounds; Toll-Like Receptors
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
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