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Estrogen receptors and galectin-3 in androgen-independent prostate cancer cells

Grant number: 20/01285-2
Support type:Regular Research Grants
Duration: December 01, 2020 - November 30, 2022
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Catarina Segreti Porto
Grantee:Catarina Segreti Porto
Home Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). São Paulo , SP, Brazil
Assoc. researchers:Gustavo José da Silva Pereira

Abstract

Prostate cancer initially responds well to androgen-deprivation therapies, but the majority of tumors evolve from an androgen-sensitive to an androgen-independent form of the disease, also known as castration-resistant prostate cancer (CRPC), which presents a poor prognosis and no effective therapy. Recent studies from our laboratory have shown the expression and the extranuclear localization of the estrogen receptors ESR1 (ERalpha) e ESR2 (ERbeta) in androgen-independent prostate cancer cell line PC-3 and DU-145, used as CRPC models. Furthermore, estrogen may play a role in PC-3 cells proliferation through a novel pathway, involving ESR2-mediated activation of ²-catenin. The activation of multiple signaling pathways is also involved in CRPC. Galectin-3 is a member of the family of animal lectins that binds alpha-galactosides. Galectin-3 is detectable in the cytosol and nucleus and also outside the cell, and may play cellular functions such as intracellular signaling pathways through protein-protein interactions, for example with beta-catenin, and with other cytoplasmic and nuclear proteins. Galectins play important roles in diverse physiological and pathological processes, including immune and inflamatory responses, cancer development, progression and metastasis. The mechanisms of regulation of galectin-3 expression are still poorly understood. The promoter region of the human galectin-3 LGALS3 gene contains several regulatory elements: five putative specificity protein 1 (Sp1) binding sites (GC boxes), five cAMP-dependent response element (CRE) motifs, four activator protein 1 (AP-1)- and one AP-4-like sites, two NF-kappaB-like sites, one sis-inducible element (SIE) and a consensus basic helix-loop-helix (bHLH) core sequence. It is important to emphasize that the estrogen receptor (ER) dimer binds to target sites on DNA either directly on ERE (estrogen response element) or indirectly through other transcription factors such as AP1 and SP1. After binding, the dimer interacts with co-regulatory proteins (chromatin modulators, co-activators and basal transcription factors), which are required for the efficient modulation of gene expression by ERs. Whether 17beta-estradiol-ERs play a role in the regulation of galectin-3 expression in prostate cells remains to be explored. Furthermore, a crosstalk between galectin-3 and ER signaling pathways could affect the progression and metastasis of the prostate cancer. Thus, the aim of this study is to investigate whether ERs could play a role in the regulation of galectin-3 expression. In addition, a crosstalk between galectin-3 and ER signaling pathways will be analyzed in the proliferation, migration and invasion of the androgen-independent prostate cancer cell lines PC-3 and DU-145. The analysis of the expression of estrogen receptors in 3D cultures from CRPC cell lines, as well to study the function of estrogen in these cultures will be determined. (AU)