PT  - JOURNAL ARTICLE
AU  - Dumstorf, Chad A.
AU  - Konicek, Bruce W.
AU  - McNulty, Ann M.
AU  - Parsons, Stephen H.
AU  - Furic, Luc
AU  - Sonenberg, Nahum
AU  - Graff, Jeremy R.
TI  - Modulation of 4E-BP1 Function as a Critical Determinant of Enzastaurin-Induced Apoptosis
AID  - 10.1158/1535-7163.MCT-10-0413
DP  - 2010 Dec 01
TA  - Molecular Cancer Therapeutics
PG  - 3158--3163
VI  - 9
IP  - 12
4099  - http://mct.aacrjournals.org/content/9/12/3158.short
4100  - http://mct.aacrjournals.org/content/9/12/3158.full
SO  - Mol Cancer Ther2010 Dec 01; 9
AB  - Enzastaurin (LY317615.HCl) is currently in a phase III registration trial for diffuse large B-Cell lymphoma and numerous phase II clinical trials. Enzastaurin suppresses angiogenesis and induces apoptosis in multiple human tumor cell lines by inhibiting protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathway signaling. PI3K/AKT pathway signaling liberates eukaryotic translation initiation factor 4E (eIF4E) through the hierarchical phosphorylation of eIF4E binding proteins (4E-BP). When hypophosphorylated, 4E-BPs associate with eIF4E, preventing eIF4E from binding eIF4G, blocking the formation of the eIF4F translation initiation complex. Herein, we show that enzastaurin treatment impacts signaling throughout the AKT/mTOR pathway leading to hypophosphorylation of 4E-BP1 in cancer cells of diverse lineages (glioblastoma, colon carcinoma, and B-cell lymphoma). Accordingly, enzastaurin treatment increases the amount of eIF4E bound to 4E-BP1 and decreases association of eIF4E with eIF4G, thereby reducing eIF4F translation initiation complex levels. We therefore chose to evaluate whether this effect on 4E-BP1 was involved in enzastaurin-induced apoptosis. Remarkably, enzastaurin-induced apoptosis was blocked in cancer cells depleted of 4E-BP1 by siRNAs, or in 4EBP1/2 knockout murine embryonic fibroblasts cells. Furthermore, eIF4E expression was increased and 4E-BP1 expression was decreased in cancer cells selected for reduced sensitivity to enzastaurin-induced apoptosis. These data highlight the importance of modulating 4E-BP1 function, and eIF4F complex levels, in the direct antitumor effect of enzastaurin and suggest that 4E-BP1 function may serve as a promising determinant of enzastaurin activity. Mol Cancer Ther; 9(12); 3158–63. ©2010 AACR.