Notch3 inhibition enhances sorafenib cytotoxic efficacy by promoting GSK3 beta phosphorylation and p21 down-regulation in hepatocellular carcinoma

作者：Giovannini Catia^*; Baglioni Michele; Toaldo Marco Baron; Ventrucci Cristiano; D' Adamo Stefania; Cipone Mario; Chieco Pasquale; Gramantieri Laura; Bolondi Luigi

来源：Oncotarget, 2013, 4(10): 1618-1631.

DOI：10.18632/oncotarget.1221

• ERK
• drug resistance
• angiogenesis
• cell proliferation
• Notch3

Sorafenib (Nexavar), a multiple kinase inhibitor, is the only clinically approved drug for patients with advanced HCC. However, its therapeutic success is limited by the emergence of drug resistance. Here we found that p21 and pGSK3 beta(Ser9) are major players in the resistance to sorafenib. We recently reported that aberrant Notch3 expression in HCC contributes to doxorubicin resistance in vitro and, therefore, we focused on the mechanisms that associate Notch3 to acquired drug resistance. In this study we first found that Notch3 inhibition significantly increased the apoptosis inducing effect of sorafenib in HCC cells via specific down-regulation of p21 and up-regulation of pGSK3 beta(Ser9). Using a mouse xenograft model we further found that Notch3 depletion combined with 21 days of sorafenib treatment exerts a substantial antitumor effect in vivo. Interestingly, we showed that, upon exposure to sorafenib treatment, Notch3 depleted xenografts maintain lower levels of p21 and higher levels of pGSK3 beta(Ser9) than control xenografts. Thus, this study demonstrated that inhibition of Notch3 signaling prevents HCC-mediate drug resistance and sensitizes HCC cells to sorafenib. Finally, we validated our in vitro and in vivo results in primary human HCCs showing that Notch3 protein expression positively correlated with p21 protein expression and negatively correlated with pGSK3 beta(Ser9) expression. In conclusion, the results presented in this study demonstrated that Notch3 silencing enhances the effect of sorafenib by overcoming drug resistance. Notch3 inhibition in combination with sorafenib can be a promising strategy for treatment of HCC.

• 出版日期2013-10