Caracterização de mecanismos moleculares associados ao gene PCA3 e novas perspectivas no Câncer de Próstata e na Doença de Alzheimer

Abstract

With the increasing longevity of the population, age-related diseases have become more and more incident, leading to great losses in patients’ life quality, among these diseases we focus in this thesis on Prostate Cancer (PCa) and Alzheimer's disease (AD), due to the possibility of sharing molecular pathways associated with the etiology of these two diseases. PCa is a highly prevalent disease worldwide, with high mortality rates, lack of therapy and specific markers for each tumor stage. Which represents a difficulty in assertive treatments for each prognosis and staging. Furthermore, despite the great advances in understanding this tumor, many knowledge gaps still need to be filled. Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the presence of amyloid plaques, neurofibrillary tangles, inflammation, oxidative damage, loss of synapses and selective neuron death. Although the inhibition of BACE1 (β-secretase) expression has been considered a therapeutic target for its prevention and treatment, the etiology of the development of AD remains a mystery. In this context, the PCA3 biomarker gene, widely studied and used as a diagnosis in PCa, is the starting point of all the hypotheses developed in this thesis and is shown to be regulated by a possible transcription factor called ARHGAP21, so we evaluated the implications of this gene in the androgen pathway and in PCA3 modulation. In addition, the genes related to PCA3, PRUNE2 and ARHGAP21 are shown to be an important factor in AD etiology. Another gene associated with PCA3 is PDCD7 (Programmed cell death 7), with probable implications in prostate cancer, and is described for the first time in this thesis, as a prognostic marker and possible therapeutic target for PCa. Therefore, this thesis is focused on the description of previously unexplored molecular mechanisms associated with PCA3, both in PCa and in AD. In Chapter I, the theoretical foundation is presented in which we describe both PCa’s and AD’s pathophysiology, the existing drug treatments, and the main therapeutic targets. We emphasize the complexity and scope of PCA3 functions, and the use of Drosophila melanogaster as a model organism for neurodegenerative diseases studies, in addition to prior knowledge for a better understanding of the work carried out in this thesis. Chapter II contains the first scientific article, already in the submission format for publication, submitted to the journal Molecular and Cellular Biochemistry, in which we evaluate the effects of ARHGAP21 as a transcription factor regulating PCA3, its effects on the proliferation and progression of PCa, as well mapping the epitopes associated with interaction with PCA3 through molecular modeling. Thus, such knowledge offers a new molecular target for therapeutic intervention and a study tool to better understand the intrinsic mechanisms of PCA3 expression and control. In Chapter III, we present the second scientific article that characterizes and describes for the first time the effects of PDCD7 on PCa and its possible use as a tumor biomarker, prognostic marker, the description of tumor pathways affected by PDCD7 silencing, and its role in communication and function through miRNAs, as well as the potential use of microRNAs in the diagnosis and therapy of PCa. It was also evaluated the PDCD7 effects on the androgen pathway associated with PCA3. Raising eyes to an increasingly elaborate understanding of the complex genesis and tumor progression. In Chapter IV, we present the third and last article that extrapolates the influence of PCA3 pathway components, such as ARHGAP21 and PRUNE2 in neurodegenerative diseases such as AD, and the modulatory power of Chlorpromazine (CPZ) on them, thus tracing a parallel between PCa and AD etiologies, paving the way for major advances in both diseases. In addition to suggesting the drug repositioning of CPZ and new studies as an antitumor drug and in the treatment of AD.