Dissertation committee:
Δημήτριος Ι. Στραβοπόδης Επίκουρος Καθηγητής (επιβλέπων), Λουκάς Χ. Μαργαρίτης Ομότιμος Καθηγητής, Ισιδώρα Ι. Παπασιδέρη Αναπληρώτρια Καθηγήτρια
Summary:
Βladder cancer is being diagnosed as the most frequent form of urinary cancer.
Aim of the present Doctorate Thesis was the investigation of activation of
apoptotic, autophagic and necrotic cell death programs, together with the
examination of structural and functional integrity of critical signaling
pathways, as essential bio-molecular responses of human bladder cancer cells to
conventional and targeted chemotherapy. The drugs examined were Cisplatin
(genotoxic-stress inducer), Bortezomib (proteasome inhibitor) and 3-BrPA
(glycolytic inhibitor), whereas the biological platform chosen to be analyzed
contained the human bladder cancer cell lines RT4, RT112, T24 and TCCSUP.
Cisplatin causes cell type-specific toxicity, inducing strong Caspase-dependent
apoptotic programs, while the Granzyme-B-dependent proteolysis of Hsp90
molecular chaperone results in Akt and XIAP structural amputation
(destabilization). Bortezomib induces grade- and p53-independent eradication of
human bladder cancer cells in vitro and in vivo, activating cell death
programs, apoptosis and/or autophagy (albeit the T24-specific autophagy
downregulation), and deregulating basic signaling axes. 3-BrPA acts in
grade-dependent, but p53-independent, manner, activating in lower doses
Caspase-mediated apoptosis and in higher concentrations PARP-dependent
necrosis. Drug administration leads to disruption of critical metabolic and
signaling pathways, severely depletes ATP cellular levels and induces a
GLUT4-specific ESS (Exon Splicing Silencing) mechanism.
Keywords:
Cancer, Urinary bladder , Chemotherapy, Proteasome, Metabolism
