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"STUDY OF THE ANDROGEN RECEPTOR ACTIVITY ON THE MODULATION OF HEPARANASE IN PROSTATE CANCER"

Grant number: 19/09693-5
Support type:Regular Research Grants
Duration: August 01, 2019 - May 31, 2022
Field of knowledge:Health Sciences - Medicine
Principal researcher:Taize Machado Augusto
Grantee:Taize Machado Augusto
Home Institution: Faculdade de Medicina de Jundiaí (FMJ). Prefeitura Municipal de Jundiaí. Jundiaí , SP, Brazil
Assoc. researchers:Gustavo Ferreira Simoes ; Nilva de Karla Cervigne

Abstract

Prostate cancer is currently the most common neoplasm in men and a recognized public health problem. The main prostate androgens are testosterone and dihydrotestosterone (DHT), stimulated and regulated by the hypothalamic-pituitary axis. Both hormones have the ability to bind to the androgen receptor (AR), however, DHT has a higher affinity for these receptors and the DHT-AR complex promotes the release of heat-shock90 proteins that enables the activation of several responsive genes to androgen that are related to the transcription of proteins responsible for the stimulation of cell proliferation.Hormone therapy, used in patients with lymph node involvement or distant metastases, consists of reducing these hormones at the level of castration. Although it is an effective treatment in the beginning, many patients evolve to the condition of castration resistant prostate cancer. The mechanisms responsible for tumor progression despite hormonal blockade have not yet been elucidated. Recent studies have shown that this is related to mutations and overexpression of AR, growth factors that activate AR, changes in co-regulatory proteins and an increase in enzymes related to metastasis and the synthesis of androgen itself. Metastasis in tumor progression is related to a number of biomolecular changes that can affect AR, signaling cascades, regulatory mechanisms and cellular apoptosis.In this study we highlight the heparanase-1 (HPSE1) enzyme that is closely related to the invasive capacity of tumor cells due to its activity related to cleavage of heparan sulfate followed by extracellular matrix remodeling (ECM) and the release of growth factors that are sequestered by this matrix, a process that contributes to an increase in tumor aggressiveness. Our previous studies on HPSE1 indicated that androgen deprivation, generated by surgical castration in rats, was correlated with an increase in the expression of HPSE-1, a fact followed by intense tissue remodeling. In addition, previous evaluation performed in our laboratory observed that prostate tumor lines with positive AR and non-responsive and negative AR, respectively, have lower and higher expression of HPSE1. The most curious of the same observation is that AR positive tumor cells, but without androgenic stimulation, had a preferentially nuclear localization pattern whereas cells without AR expression, the pattern was more cytoplasmic. Much is known in spite of the extracellular functions of HPSE1, but a new possible function for its nuclear localization is already known, and goes counter to its enzymatic activity that is related to tumor progression. In this sense, this project aims to investigate the participation of androgen receptor activity on the modulation of HPSE1 in prostatic tumor lines (LNCaP and DU-145) through expression analysis and focusing on the localization of HPSE1, in addition to possible changes in proliferative processes and tumor invasiveness. In addition, we will also try to verify a possible genomic interaction between the AR and the promoter region of HPSE1. For this, immunoprecipitation assays will be used to investigate a possible interaction of the androgen receptor in the HPSE1 gene, in addition to immunofluorescence assays, Western blotting, real-time RT-PCR and matrigel invasion, to better understand biology and the microenvironment of prostate cancer metastasis and its susceptibility to the anti-androgenic treatments currently in use in the medical clinic. (AU)