Dottorato in BIOCHIMICA

Titolo della tesi: Protein Disulfide-Isomerase A3 (PDIA3): a multifunctional protein as therapeutic target in several human diseases

Abstract Protein disulfide-isomerase associated 3 (PDIA3) plays an important role in the natural history of cancer and the development of therapeutic processes. As an ER chaperone, PDIA3 participates in MHC class I molecule assembly, regulates tumor cell immunogenicity, facilitates new glycoprotein synthesis. It functions as a 1,25D3-MARRS receptor, regulates gene transcription, binds to STAT3 and NF-κB, enhances MMC-induced DNA cross-linking and is involved in DNA repair processes and cytoskeletal remodeling. Numerous studies have demonstrated that PDIA3 plays a significant role in tumor development and chemoresistance in a wide variety of cancers, and it is involved in many other human pathologies, such as, neurodegenerative diseases, metabolic diseases, musculoskeletal system conditions, airway inflammations, platelet aggregation and viral infections. These crucial roles and their regulatory pathways might provide a framework for the comprehensive understanding of PDIA3 in human diseases, which might indicate its potential as a therapeutic target for cancer and other human diseases' treatment. During my thesis work, we deepened the role of punicalagin as a PDIA3 inhibitor, performing a comparative study with PDIA1. We also discovered two novelties, pulegone and myristicin, in terms of potentially leading compounds for PDIA3 inhibition. Our knowledge in terms of PDIA3’s binding sites and PDIA3’s ligands as potential inhibitors have allowed us to start a drug design project that is still underway to synthetically obtain the first specific inhibitor for PDIA3 that can meet the criteria of a good drug (Lipinsky’s rule of five). Furthermore, as proof of the value of having a PDIA3 inhibitor we used punicalagin, the best specific inhibitor of PDIA3 known so far, in two cellular models, prostate cancer and glioblastoma. Preliminary results on glioblastoma highlighted the punicalagin, as PDIA3’s inhibitor, to be a coadjutant in glioblastoma treatment with temozolomide. Our future goal will be to demonstrate, using in vitro and in vivo models, the role of PDIA3 synthetic inhibitors that can be implemented in new therapies for human diseases.