Activation of the downstream akt and mitogen-activated protein kinases is associated with development and progression of prostate cancer to the lethal androgen-independent state. However, the causal role of these downstream kinases in androgen-independent prostate cancers is unknown. In this study, activation and requirements of akt and mitogen-activated protein kinase (erk, p38, and jnk) signaling for the survival and proliferation of five malignant human cell lines encompassing the spectrum of androgen-independent prostate cancers was compared with the activation and requirements in normal prostate epithelial cells. Using Western blotting with phospho-antibodies, we detected differential activation in exponentially growing, growth factor-deprived, and restimulated cultures of malignant versus normal cells. The inhibition of erk, p38, jnk, and akt with U0126, SB203580, SP600125, and Akt inhibitor, respectively, document that normal cells require simultaneous erk and jnk signaling for survival, plus akt signaling for proliferation. In malignant cells, however, only jnk inhibition as monotherapy produces a consistent apoptotic response, although the combinatorial inhibition of jnk, erk, p38 plus akt results in statistically enhanced apoptosis. These results demonstrate that prostate cancer progression to a lethal androgen-independent state involves the acquisition of an enhanced redundancy in downstream survival signaling.