TY - JOUR
T1 - SAHA-sensitized prostate cancer cells to TNFα-related apoptosis-inducing ligand (TRAIL)
T2 - Mechanisms leading to synergistic apoptosis
AU - Lakshmikanthan, Vijayabaskar
AU - Kaddour-Djebbar, Ismail
AU - Lewis, Ronald W.
AU - Kumar, M. Vijay
PY - 2006/7/1
Y1 - 2006/7/1
N2 - Treatment of cancer cells with histone deacetylase inhibitors (HDACi) such as suberolylanilide hydroxamic acid (SAHA) activates genes that promote apoptosis. To enhance proapoptotic efficiency, SAHA has been used in combination with radiation, kinase inhibitors and cytotoxic drugs. Although several prostate cells respond to TNFα-Related Apoptosis-Inducing Ligand (TRAIL), LNCaP are resistant. This model system was utilized to examine the advantages of combined treatment with SAHA and TRAIL. In LNCaP cells, TRAIL induced synergistic apoptosis when combined with even with the lowest dose SAHA. Treatment with caspase inhibitor confirmed that SAHA-induced apoptosis was mediated through caspases. In addition to induction of apoptosis, SAHA and TRAIL decreased the levels of proapoptotic proteins IKKα, IKKβ and IKKγ, suggesting that SAHA treatment may reduce the activity of NFκB. However, assay for NFκB luciferase reporter activity showed highly significant increase in SAHA-treated cells, supporting earlier suggestions that HDACi promotes NFκB transcriptional activity. Further analyses to determine the mechanisms by which the combination of SAHA and TRAIL led to synergistic apoptosis indicated that the apoptotic response of LNCaP is due to a complex regulation of death receptor pathway and alterations of NFκB activity at several regulatory steps.
AB - Treatment of cancer cells with histone deacetylase inhibitors (HDACi) such as suberolylanilide hydroxamic acid (SAHA) activates genes that promote apoptosis. To enhance proapoptotic efficiency, SAHA has been used in combination with radiation, kinase inhibitors and cytotoxic drugs. Although several prostate cells respond to TNFα-Related Apoptosis-Inducing Ligand (TRAIL), LNCaP are resistant. This model system was utilized to examine the advantages of combined treatment with SAHA and TRAIL. In LNCaP cells, TRAIL induced synergistic apoptosis when combined with even with the lowest dose SAHA. Treatment with caspase inhibitor confirmed that SAHA-induced apoptosis was mediated through caspases. In addition to induction of apoptosis, SAHA and TRAIL decreased the levels of proapoptotic proteins IKKα, IKKβ and IKKγ, suggesting that SAHA treatment may reduce the activity of NFκB. However, assay for NFκB luciferase reporter activity showed highly significant increase in SAHA-treated cells, supporting earlier suggestions that HDACi promotes NFκB transcriptional activity. Further analyses to determine the mechanisms by which the combination of SAHA and TRAIL led to synergistic apoptosis indicated that the apoptotic response of LNCaP is due to a complex regulation of death receptor pathway and alterations of NFκB activity at several regulatory steps.
KW - HDAC
KW - IKK
KW - Prostate cancer
KW - SAHA
UR - http://www.scopus.com/inward/record.url?scp=33646517941&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646517941&partnerID=8YFLogxK
U2 - 10.1002/ijc.21824
DO - 10.1002/ijc.21824
M3 - Article
C2 - 16450389
AN - SCOPUS:33646517941
SN - 0020-7136
VL - 119
SP - 221
EP - 228
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 1
ER -