Aurora Kinase A expression predicts platinum-resistance and adverse outcome in high-grade serous ovarian carcinoma patients

High-Grade Serous Ovarian Carcinoma (HGSOC) is the predominant histotype of epithelial ovarian cancer (EOC), characterized by advanced stage at diagnosis, frequent TP53 mutation, rapid progression, and high responsiveness to platinum-based-chemotherapy. To date, standard first-line-chemotherapy in advanced EOC includes platinum salts and paclitaxel with or without bevacizumab. The major prognostic factor is the response duration from the end of the platinum-based treatment (platinum-free interval) and about 10-0 % of EOC patients bear a platinum-refractory disease or develop early resistance (platinum-free interval shorter than 6 months). On these bases, a careful selection of patients who could benefit from chemotherapy is recommended to avoid unnecessary side effects and for a better disease outcome. In this retrospective study, an immunohistochemical evaluation of Aurora Kinase A (AURKA) was performed on 41 cases of HGSOC according to platinum-status. Taking into account the number and intensity of AURKA positive cells we built a predictive score able to discriminate with high accuracy platinum-sensitive patients from platinum-resistant patients (p < 0.001). Furthermore, we observed that AURKA overexpression correlates to worse overall survival (p = 0.001; HR 0.14). We here suggest AURKA as new effective tool to predict the biological behavior of HGSOC. Particularly, our results indicate that AURKA has a role both as predictor of platinum-resistance and as prognostic factor, that deserves further investigation in prospective clinical trials. Indeed, in the era of personalized medicine, AURKA could assist the clinicians in selecting the best treatment and represent, at the same time, a promising new therapeutic target in EOC treatment

Internalization of HIV-1 Tat requires cell surface heparan sulfate proteoglycans

4nonenoneTYAGI M.; RUSNATI M.; PRESTA M.; GIACCA M.Tyagi, M.; Rusnati, M.; Presta, M.; Giacca, Maur

Role of endothelial cell extracellular signal-regulated kinase1/2 in urokinase-type plasminogen activator upregulation and in vitro angiogenesis by fibroblast growth factor-2.

Downstream signaling triggered by the binding of fibroblast growth factor-2 (FGF2) to its tyrosine-kinase receptors involves the activation of mitogen-activated protein kinase kinase (MEK) with consequent phosphorylation of extracellular signal-regulated kinases (ERKs). Here we demonstrate that FGF2 induces ERK(1/2) activation in bovine aortic endothelial (BAE) cells and that the continuous presence of the growth factor is required for sustained ERK(1/2) phosphorylation. This is prevented by the MEK inhibitors PD 098059 and U0126, which also inhibit FGF2-mediated upregulation of urokinase-type plasminogen activator (uPA) and in vitro formation of capillary-like structures in three-dimensional type I collagen gel. Various FGF2 mutants originated by deletion or substitution of basic amino acid residues in the amino terminus or in the carboxyl terminus of FGF2 retained the capacity to induce a long-lasting activation of ERK(1/2) in BAE cells. Among them, K128Q/R129Q-FGF2 was also able to stimulate uPA production and morphogenesis whereas R129Q/K134Q-FGF2 caused uPA upregulation only. In contrast, K27,30Q/R31Q-FGF2, K128Q/K138Q-FGF2 and R118,129Q/K119,128Q-FGF2 exerted a significant uPA-inducing and morphogenic activity in an ERK(1/2)-dependent manner only in the presence of heparin. Furthermore, no uPA upregulation and morphogenesis was observed in BAE cells treated with the deletion mutant Δ27-32-FGF2 even in the presence of soluble heparin. Thus, mutational analysis of FGF2 dissociates the capacity of the growth factor to induce a persistent activation of ERK(1/2) from its ability to stimulate uPA upregulation and/or in vitro angiogenesis. In conclusion, the data indicate that ERK(1/2) phosphorylation is a key step in the signal transduction pathway switched on by FGF2 in endothelial cells. Nevertheless, a sustained ERK(1/2) activation is not sufficient to trigger uPA upregulation and morphogenesis. FGF2 mutants may represent useful tools to dissect the signal transduction pathway(s) mediating the complex response elicited by an angiogenic stimulus in endothelial cells