PI3 Kinase inhibition on TRAIL-induced apoptosis correlates with androgen-sensitivity and p21 expression in prostate cancer cells

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 p21(waf1, 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.

Paradoxical and contradictory effects of imatinib in two cell line models of hormone-refractory prostate cancer

“…In case of DU145 cells, the increased expression of p21 is consistent with blockage of cell cycle since the number of proliferating viable cells is diminished after administration of imatinib. On the other hand, there are reports stating that p21 confers resistance to imatinib induced‐apoptosis in human chronic myeloid leukemia cells , and that it induces resistance to treatment in cases of PCa . Therefore, it is liable to assume that a similar mechanism is occurring in PC3 cells, which would explain the increased cell viability following treatment with imatinib.…”

Androgen receptor (AR) positive vs negative roles in prostate cancer cell deaths including apoptosis, anoikis, entosis, necrosis and autophagic cell death

“…Kadowaki et al found that the AR-positive LNCaP cells were resistant to TRAIL-induced apoptosis, while the AR-negative PC-3 cells were sensitive 87 , suggesting AR might play negative roles in this type of apoptosis. Rokhlin et al also revealed that increased AKT might suppress the androgen-inhibited apoptosis 52 .…”

An Antidepressant Drug Increased TRAIL Receptor-2 Expression and Sensitized Lung Cancer Cells to TRAIL-induced Apoptosis

“…It is able to target a wide range of tumor cells without affecting normal cells [ 11 ]. TRAIL-mediated cancer cell killing can occur via both extrinsic and intrinsic apoptotic pathways [ 12 ]. TRAIL triggers apoptotic signals through bindings to its death receptors, (DR4 and DR5) [ 12 , 13 ].…”

“…TRAIL-mediated cancer cell killing can occur via both extrinsic and intrinsic apoptotic pathways [ 12 ]. TRAIL triggers apoptotic signals through bindings to its death receptors, (DR4 and DR5) [ 12 , 13 ]. The interaction between TRAIL and its receptors triggers the recruitment of the Fas-associated death domain (FADD), facilitating the subsequent recruitment of procaspase-8 [ 14 ].…”