Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state

The mechanisms by which prostate cancer (PCa) cells progress to a hormone r efractory state are poorly understood. The progression process under androg en ablation conditions involves the survival of at least a portion of malig nant cells and their eventual proliferation in an androgen-independent mann er. The goal of this study was to investigate the role of PI3K signaling in such a progression. Using an in vitro model of androgen ablation, we show that after removal of androgen support, the human PCa cell line LNCaP initi ally arrested in G, and trans-differentiated into neuroendocrine-like cells that eventually resumed androgen-independent proliferation. Both acute and chronic androgen ablation resulted in an increase in basal levels of P13K and Akt activity, which were sustained throughout the progression process. Under these conditions, inhibition of P13K, pharmacologically or with ectop ic expression of PTEN, arrested cell proliferation and blocked progression to the androgen-independent state. In contrast, LNCaP cells in the presence of androgens were marginally sensitive to P13K inhibition. During the chro nic stage of androgen deprivation, androgen-independent proliferation corre lated with diminished p27(kip1) protein levels, whereas P13K and Akt activi ty remained elevated. At this stage, P13K inhibition rapidly triggered accu mulation of p27(kip1), cell cycle arrest, and cell death. P13K modulated p2 7(kip1) levels at least in part by regulating its rate of degradation. Take n together, these data show that androgen ablation alone can increase P13K- Akt activation, which supports survival after acute androgen ablation and p roliferation during chronic androgen deprivation. Successful progression to the androgen-independent state in the LNCaP cell line model requires intac t P13K signaling.