PI3 Kinase inhibition on TRAIL-induced apoptosis correlates with androgen-sensitivity and p21 expression in prostate cancer cells |
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Authors: | Yoshihiko Kadowaki Nikhil S Chari Albert E K Teo Akihiko Hashi Kevin B Spurgers Timothy J McDonnell |
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Institution: | (1) Department of Hematopathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, P.O. Box 89, Houston, TX 77030, USA; |
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Abstract: | TNF-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in many types of cancer cells. TRAIL is considered a therapeutic
target, therefore, it was of interest to examine molecular mechanisms that may modulate sensitivity to TRAIL signaling in
prostate cancer cells. LNCaP cells were found to be relatively resistant to TRAIL induced cell death while PC3 cells were
sensitive. PI3-kinase (PI3 K) inhibitors were able to render LNCaP cells sensitive to TRAIL but conferred resistance to PC3
cells. PI3 K inhibitors were associated with an increase in p21waf1, cip1 expression in PC3 cells where as p21 decreases in LNCaP cells suggesting that p21 may impart TRAIL resistance. Since androgen
receptor (AR) signaling can be modulated by AKT, and p21 is an AR responsive gene, the impact of PI3 K inhibition on TRAIL
sensitivity was evaluated in AR transfected PC3 cells (PC3AR). The expression of AR was significantly downregulated by PI3 K
inhibition in LNCaP cells, which have an intact AR signaling axis. PC3AR cells expressed higher levels of p21 protein and
were relatively resistant to TRAIL compared to control cells. Finally, using adenoviral p21 gene transfer we directly demonstrated
that p21 can confer resistance to TRAIL-induced cell death. These results suggest that TRAIL resistance is not regulated simply
by a PI3 K/AKT survival pathway associated with inactivating PTEN mutations but may also be modulated by downstream AR responsive
targets such as p21. These findings may have significant clinical implications for the utility of TRAIL in the management
of prostate cancer. |
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