The phosphatidylinositol 3 '-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells

Intracellular signaling pathways that mediate survival of prostate carcinom a (PCa) cells are poorly understood. We examined the potential role of the phosphatidylinositol 3' kinase (PI3K) pathway as a mediator of cell surviva l in LNCaP human PCa cells, which express a variety of properties character istic of human prostate cancer. LNCaP cell cultures rapidly became apoptoti c when treated with the specific PI3K inhibitors, wortmannin and LY294002. In contrast, apoptosis was not induced when the cells were treated with: (a ) rapamycin, an inhibitor of the ribosomal S6 kinase pp70(86K), which acts downstream of PI3K; (b) PD98059, a specific inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (Erk/MAPK) kinase (MEK); or (c) the antiandrogen, Casodex; or when the cells were cultured un der androgen-depleted conditions, Apoptosis induced by PI3K inhibition was attenuated by: (a) dihydrotestosterone; or (b) the ErbB1 activating ligands [epidermal growth factor (EGF), transforming growth factor a, or heparin-b inding EGF-like growth factor], In response to ErbB1 activation by ligand, the p85 regulatory subunit of PI3K associated specifically with ErbB3 but n ot detectably with ErbB1, The anti-apoptotic effect of ErbB1 activation was significantly reduced when cells were treated simultaneously with wortmann in and PD98059, These data indicate that survival signals can be evoked in LNCaP cells by several distinct pathways and can be triggered by nuclear an d cell-surface receptors, Constitutive signaling through the PI3K pathway i s required to prevent cell death in LNCaP, whereas activation of the Erk/MA PK and androgen response pathways is not obligatory for cell survival. Thes e results also show that survival signals, as distinguished from mitogenic signals, can be evoked in PCa cells by ErbB1 ligands known to be synthesize d within the human prostate.