A defining characteristic of solid tumors is the capacity to divide aggressively and disseminate under conditions of nutrient deprivation, limited oxygen availability, and exposure to cytotoxic drugs or radiation. Survival pathways are activated within tumor cells to cope with these ambient stresses. We here describe a survival pathway activated by the anti-cancer drug docetaxel in prostate cancer cells. Docetaxel activates STAT3 phosphorylation and transcriptional activity, which in turns induces expression of the PIM1 gene, encoding a serine-threonine kinase activated by many cellular stresses. Expression of PIM1 improves survival of docetaxel-treated prostate cancer cells, and PIM1 knockdown or expression of a dominant-negative PIM1 protein sensitize cells to the cytotoxic effects of docetaxel. PIM1 in turn mediates docetaxel-induced activation of NFB transcriptional activity, and PIM1 depends in part on RELA/p65 proteins for its prosurvival effects. The PIM1 kinase plays a critical role in this STAT3 3 PIM1 3 NFB stress response pathway and serves as a target for intervention to enhance the therapeutic effects of cytotoxic drugs such as docetaxel.A defining characteristic of solid tumors is the capacity to divide aggressively and metastasize under conditions of nutrient deprivation and limited oxygen availability. These microenvironmental stresses arise from inadequate perfusion as the primary tumor rapidly outgrows its initial blood supply and from dramatic structural abnormalities of tumor vessels that lead to aberrant microcirculation. Survival pathways are activated within tumor cells to cope with these ambient stresses. Examples include stress pathways that respond to hypoxia (1), oxidative stress (2), and unfolded protein/endoplasmic reticulum stresses (3). In addition to these microenvironmental stresses, anti-cancer treatment can cause additional stresses to cancer cells. These added insults call forth additional responses that can augment the survival mechanisms of the malignant cells and impair overall cell kill. Key participants in stress response pathways induced by cytotoxic drugs include AKT-and other kinase-dependent pathways (4 -8), NFB 2 pathways (9), and mediators of DNA repair (10).Among the potential survival proteins in cancer cells are the PIM family of kinases, including the PIM1, PIM2, and PIM3 genes. These small, cytoplasmic serine-threonine kinases function as true oncogenes, promoting the development of cancer in animal models, either alone (11) or synergistically with other oncogenes, such as MYC (12). In normal and malignant cells, PIM kinases are highly regulated at the transcriptional level. Expression is induced by many cellular stresses, including cytokines (13), oncogenes (14), hypoxia (15), heat shock (16), and toxin exposure (17). In addition, PIM kinases are constitutively expressed in a variety of leukemias and lymphomas (18), in head and neck squamous cell carcinomas (19), and in prostate cancer (20 -22). Therefore, PIM kinases may mediate in part the process of carcino...