Role of dysfunctional HDL and oxidative stress in bladder cancer.

Epidemiological studies suggest associations between type 2 diabetes mellitus and bladder cancer. Several potential mechanisms may explain the increased bladder cancer burden in DM patients. Hyperglycaemia is associated with dysregulation of cell intracellular metabolism and alterations of lipoprotein metabolism and oxidative stress. In fact, previous studies have shown that levels and functions of circulating lipoprotein are modified in DM patients. Dysfunctional HDL including glycated and oxidized HDL are described in patients with type 2 diabetes mellitus. We evaluated the effect of normal HDL and glycated HDL on cell proliferation and oxidative stress of J82 bladder cancer cells. We also studied the effect of HDL on cholesterol influx and efflux. In addition, the expression of proteins involved in cholesterol transport (ABCA1, SRB1, ABCG1) by western blot analysis was studied. Our results demonstrate that HDL incubated 7 days at 37⁰C with increasing concentrations of glucose (30-100mM) have lower levels of free amino groups with respect to untreated HDL. The decrease realized at a higher extent using glucose 100 mM therefore this concentration was used to investigate the effect of glycated HDL on J82 cells. Levels of TBARS and conjugated dienes were higher in G-HDL compared with N-HDL. These results demonstrate that lipid peroxidation occurs during glycation treatment. The enzyme activity of paraoxonase (HDL-PON1) was significantly decreased in G-HDL . High markers of lipid peroxidation and a decrease of Paraoxonase activity are described in dysfunctional HDL. The study of the effect of Normal HDL and glycated HDL (G-HDL) on J82 cells in culture has shown that both N-HDL and G-HDL promote cell proliferation and increase the levels of intracellular reactive oxygen species (ROS) during incubation with the oxidizing agent tert-butyl hydroperoxide. The increase of intracellular ROS was associated to higher levels of TBARS in cells incubated with G-HDL than N-HDL. The increase in oxidative stress in cells incubated with N-HDL was associated with alterations of cholesterol homeostasis. In detail Cholesterol efflux was increased, on the contrary cholesterol influx was significantly decreased in cells incubated with G-HDL. Expression of receptor protein SR-B1 and ABCG1 was increased. The higher expression of SR-B1 in cells incubated with G-HDL suggests that dysfunctional HDL could affect cholesterol homeostasis in J82 bladder cancer cells. These results suggest that HDL-based treatments should be considered for treatment of bladder cancer.

Il cancro alla vescica urinaria (BC) è uno dei tumori più comuni alla vescica urinaria, sia per le donne che per gli uomini, nei Paesi occidentali. Studi in vitro e in vivo suggeriscono che alti livelli di specie reattive dell’ossigeno (ROS) e le specie reattive dell’azoto (RNS) e lo stress ossidativo hanno un ruolo cruciale nel cancro dell’uomo. Basse concentrazioni di ROS e di RNS sono indispensabili per la sopravvivenza e la proliferazione delle cellule. Comunque, alte concentrazioni di ROS e d RNS possono esercitare un effetto citotossico. Un aumento dello stress ossidativo è il risultato o di un aumento della produzione di ROS/RNS o una diminuzione del meccanismo di difesa antiossidante. Una ricerca letteraria è stata portata avanti su PubMed, Medline, e Google Scholar con articoli in inglese pubblicati fino a Maggio 2018 che usano le seguenti parole chiave: stress ossidativo, antiossidanti, specie reattive dell’ossigeno, perossidazione lipidica, paraoxonasi, cancro alla vescica urinaria, ossido di azoto. Dati letterari dimostrano che BC è associato allo stress ossidativo e con uno sbilancio trae enzimi ossidanti e antiossidanti. I marcatori della perossidazione lipidica, l’ossidazione delle proteine e degli acidi nucleici sono significativamente più alte nei tessuti di pazienti con il cancro alla vescica comparati a gruppi di controllo. Una diminuzione dell’attività di enzimi antiossidanti (superossido dismutasi, catalasi, glutatione, e paraoxonasi) è stata dimostrata. Lo sbilancio tra ossidanti e antiossidanti potrebbe avere un potenziale ruolo nell’eziologia e nella progressione del cancro alla vescica.