The PIM1 Kinase Is a Critical Component of a Survival Pathway Activated by Docetaxel and Promotes Survival of Docetaxel-treated Prostate Cancer Cells

Abstract

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...

Pim-1 controls NF-κB signalling by stabilizing RelA/p65

“…In this context, a recent study showed that protective effect of Pim-1 depends, at least in part, upon NF-kB activity; however, there was no evidence that Pim-1 directly affects NF-kB. 28 This study is the first to show that Pim-1 directly activates NF-kB signalling by phosphorylating RelA/p65 at Ser276. Intriguingly, reconstitution of RelA/p65 À/À MEFs with various serine to alanine substituted mutants of p65 recently was found to completely rescue TNF-a-induced IL-6 production with S529A, S536A, and S529A/S536A mutants, whereas S276A was completely unresponsive to TNF-a to induce IL-6 expression, indicating that this phosphorylation is critical for RelA/p65 activity.…”

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

“…These data may account for accelerated hepatocarcinogenesis in Pim-3 transgenic mice. However, several lines of evidence indicate the potential involvement of other Pim kinases, Pim-1 and Pim-2, in NF-kB activation (Hammerman et al, 2004;Zemskova et al, 2008). Thus, it still remains to be investigated whether the Pim-3 transgene can induce ROS generation in a similar manner as the IKKb deletion.…”

“…The production of TNF-a was regulated at several steps and the first one was at the transcription level, governed by transcription factors, such as NF-kB and Activator protein-1AP-1 (Manna et al, 2000;Udalova and Kwiatkowski, 2001;Chung et al, 2007). As Pim-1 can enhance NF-kB transcriptional activity (Zemskova et al, 2008), Pim-3 might be able to similarly activate NF-kB, thereby inducing TNFa expression.…”

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

“…Importantly, NO produced by NOS has been shown to bind nitrosylates ASK1 and JNK, inactivating their apoptotic cascade (59,60). Another mechanism of drug resistance that may be involved is PIM1 activation, which has been shown to be activated by docetaxel (61). PIM1 promotes cell survival by were randomized and treated with vehicle, docetaxel, or combination therapy (docetaxel þ NOS inhibition therapy).…”