Abstract 3316: An alpha-secretase inhibitor decreases glioma stem cell growth by inhibiting the Notch pathway and LMW Cyclin E

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 8_Supplement; p. 3316
• Main Authors: Floyd, Desiree H., Kefas, Benjamin, Seleverstov, Olexsandr, Dominguez, Charli, Comeau, Laurey, Purow, Benjamin W.
• Format: Journal Article
• Language: English
• Published: 15.04.2011
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-3316

Abstract The Notch pathway is deregulated in glioblastoma. Previous work suggests the inhibition of this pathway will have therapeutic benefits. The only inhibitors of Notch available block the gamma-secretase enzymatic complex necessary for processing Notch into the active form. However, Notch is also cleaved by alpha-secretase outside the plasma membrane, with the sheddases ADAM10 and 17. INCB3619 is a potent inhibitor of both ADAM10 and 17, and has been shown to inhibit growth of MCF-7 breast tumor cells when used with lapatinib. In this work, INCB3619 was used to inhibit endogenous Notch cleavage and downstream CBF-1 reporter activity in 0308 and 0822 human glioma stem cell lines. A microarray analysis of INCB3619 vs. DMSO treatment of 0308 cells identified many downregulated Notch pathway targets, but also identified new targets of INCB3619, such as CHI3L1/YKL40, an important prognostic indicator of many inflammatory diseases. Treatment of 0308 and 0822 glioma stem lines with INCB3619 inhibited their growth in culture due to a cell cycle arrest in G1 and a decrease in S phase cells. Growth inhibition by INCB3619 can be rescued with transfection of the active form of two Notch family members, NICD1 and 2. The growth inhibition of INCB3619 treated glioma stem cells is also stems from a shift in Cyclin E expression from a hyperactive low-molecular-weight form to the usual high-molecular-weight form. Also, INCB3619 induces higher expression of both p53 and p21, which can inhibit Cyclin E. Unlike with INCB3619, The treatment of glioma stem cells with DAPT, a well-known and potent gamma secretase inhibitor that cleaves Notch downstream of ADAM10 and 17, does not have a noticeable effect on Cyclin E processing or p21/p53 expression. INCB3619 therefore decreases glioma stem cell growth partly through a mechanism of Notch inhibition and also through inhibition of production of the hyperactive low-molecular-weight form of Cyclin E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3316. doi:10.1158/1538-7445.AM2011-3316