PT  - JOURNAL ARTICLE
AU  - Inoue, Satoshi
AU  - Harper, Nick
AU  - Walewska, Renata
AU  - Dyer, Martin J.S.
AU  - Cohen, Gerald M.
TI  - Enhanced Fas-associated death domain recruitment by histone deacetylase inhibitors is critical for the sensitization of chronic lymphocytic leukemia cells to TRAIL-induced apoptosis
AID  - 10.1158/1535-7163.MCT-09-0451
DP  - 2009 Nov 01
TA  - Molecular Cancer Therapeutics
PG  - 3088--3097
VI  - 8
IP  - 11
4099  - http://mct.aacrjournals.org/content/8/11/3088.short
4100  - http://mct.aacrjournals.org/content/8/11/3088.full
SO  - Mol Cancer Ther2009 Nov 01; 8
AB  - Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by failure of mature lymphocytes to undergo apoptosis. CLL cells are inherently resistant to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Pretreatment with histone deacetylase inhibitors (HDACi) sensitizes CLL cells to TRAIL-mediated apoptosis primarily via TRAIL-R1 and offers a novel approach for the therapy of CLL and other malignancies. Depsipeptide (romidepsin), a HDACi, did not enhance TRAIL binding to TRAIL-R1, TRAIL-R1 aggregation, or internalization of TRAIL-R1, but it enhanced Fas-associated death domain protein (FADD) recruitment to TRAIL-R1 in the death-inducing signaling complex. Cotreatment with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, dramatically inhibited the HDACi-mediated increase in FADD recruitment and sensitization to TRAIL-induced apoptosis and both of these were reversed by PKC inhibitors. Thus, enhanced FADD recruitment is a critical step in HDACi-mediated sensitization of CLL cells to TRAIL-induced apoptosis and this step is differentially affected by HDACi and phorbol 12-myristate 13-acetate. Using biotinylated TRAIL and streptactin-tagged TRAIL, we have identified several novel TRAIL receptor interacting proteins, including PKCβ, lymphocyte-specific protease-1, Lyn, and Syk. These molecules may play an as yet unappreciated role in TRAIL signaling in CLL cells and inhibition of one or more of these kinases/phosphatases may provide a novel target to overcome TRAIL resistance. [Mol Cancer Ther 2009;8(11):3088–97]© 2009 American Association for Cancer Research.