The Akt inhibitor triciribine sensitizes prostate carcinoma cells to TRAIL-induced apoptosis.
Aberrant PI3K/Akt signaling has been implicated in many human cancers, including prostate carcinomas. Currently different therapeutic strategies target the inhibition of this survival pathway. The nucleoside analog triciribine (TCN), which was initially described as a DNA synthesis inhibitor, has recently been shown to function as an inhibitor of Akt. Here, we demonstrate that TCN inhibits Akt phosphorylation at Thr308 and Ser473 and Akt activity in the human prostate cancer cell line PC-3. In addition, TCN sensitized PC-3 cells to TRAIL- and anti-CD95-induced apoptosis, whereas the cells remained resistant to DNA damaging chemotherapeutics. The observed sensitization essentially depended on the phosphorylation status of Akt. Thus, prostate cancer cell lines displaying constitutively active Akt, e.g. PC-3 or LNCaP, were sensitized to death receptor-induced apoptosis. Most importantly with respect to therapeutic application, derivatives of both TCN and TRAIL are already tested in current clinical trials. Therefore, this combinatorial treatment might open a promising therapeutic approach for the elimination of hormone-refractory prostate cancers, which are largely resistant to conventional DNA damaging anticancer drugs or irradiation.
Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
Alexandra
A
Dieterle
Ronald
R
Orth
Merle
M
Daubrawa
Antje
A
Grotemeier
Sebastian
S
Alers
Susanne
S
Ullrich
Reiner
R
Lammers
Sebastian
S
Wesselborg
Björn
B
Stork
D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014145:Trail Making Test; D014407:Tumor Cells, Cultured
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D034741:RNA, Small Interfering; D012263:Ribonucleosides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C023764:triciribine; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases