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Tesi etd-06272011-190433

Thesis type
Tesi di laurea specialistica LC6
email address
Effects of membrane gamma-glutamyltranspeptidase activity on expression, redox status and activation of EGFR in prostate cancer cells
Corso di studi
relatore Prof. Pompella, Alfonso
Parole chiave
  • egfr
  • ggt
  • glutathione
  • prostate cancer
  • trafficking
  • redox modulation
Data inizio appello
Data di rilascio
Riassunto analitico
Regulation of signal transduction systems by redox-sensing mechanisms is now considered as a general means of overall control on cellular “traditional” signalling, based on protein phosphorylation/dephosphorylation equilibrium. Different redox alterations of thiols in cysteine residues of a protein can induce different functional states, thus acting as a fine post-translational modification. At present, available data mostly extrapolate from model systems employing an exogenous source of prooxidants (e.g., various concentrations of hydrogen peroxide).
A novel redox factor of enzymatic nature is gamma-glutamyltranspeptidase (GGT), an ectoenzyme in charge of glutathione catabolism and expressed in a wide range of human epithelial cells as well as cancer cells. Indeed, one of the roles of GGT-dependent production of prooxidants, is modulation of redox status of cell surface protein thiols, as previously described for TNFR1 (tumor necrosis factor 1). Consequently, the present study aims to verify the effects of GGT activity on redox status and function of another transmembrane receptor, i.e. EGFR (epidermal growth factor receptor). Although present in normal cells, EGFR is overexpressed in a variety of tumor cell lines and is currently an important target of cancer therapy. However, despite available data indicate that EGFR expression is generally associated to unfavorable prognosis, much is still to be clarified with respects to other mechanisms concurring with EGFR expression in determining EGFR signalling output. Indeed, one of such mechanisms might consist in redox phenomena.
Consistently, our preliminary results show that GGT determines a more oxidized status of the EGFR and this, in turn, also provokes an aberrant reduced phosphorylation of the tyr-1068 residue of the receptor. This can prevent the ubiquitinylation and degradation of EGFR, wich may be sorted to the nucleus instead, where it is known to activate signalling pathways implicated in tumorigenesis and resistance to DNA damaging radiation and alkylating anti-cancer agents. Indeed, in our model system, GGT seems to enhance the localization of the receptor in the perinuclear compartment. Moreover, our data demonstrate that the basal expression of the EGFR is reduced under the prooxidant effect of GGT. These findings may imply that an endogenous source of hydrogen peroxide can shift the balance of the EGFR signalling network acting on several levels, e.g. the receptor trafficking and down-regulation. A better understanding of such processes may be crucial to unravel mechanisms underlaying cancer progression and treatment resistance and may also define new therapeutic targets.