JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate

University of Massachusetts Medical School, Worcester, MA 01605, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2012; 109(30):12046-51. DOI: 10.1073/pnas.1209660109
Source: PubMed


The c-Jun NH(2)-terminal kinase (JNK) signal transduction pathway is implicated in cancer, but the role of JNK in tumorigenesis is poorly understood. Here, we demonstrate that the JNK signaling pathway reduces the development of invasive adenocarcinoma in the phosphatase and tensin homolog (Pten) conditional deletion model of prostate cancer. Mice with JNK deficiency in the prostate epithelium (ΔJnk ΔPten mice) develop androgen-independent metastatic prostate cancer more rapidly than control (ΔPten) mice. Similarly, prevention of JNK activation in the prostate epithelium (ΔMkk4 ΔMkk7 ΔPten mice) causes rapid development of invasive adenocarcinoma. We found that JNK signaling defects cause an androgen-independent expansion of the immature progenitor cell population in the primary tumor. The JNK-deficient progenitor cells display increased proliferation and tumorigenic potential compared with progenitor cells from control prostate tumors. These data demonstrate that the JNK and PTEN signaling pathways can cooperate to regulate the progression of prostate neoplasia to invasive adenocarcinoma.

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Available from: Richard A Flavell
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    • "On the other hand, activating mutations in PDK-1 or AKT-1 may not be sufficiently strong to sequester DAF-16; JNK activation can override this inhibition. It is also possible that DAF-18 and JNK-1 interact independent of PDK-1 or its downstream kinases, by some mechanism as indicated in other systems (Vivanco et al., 2007; Hubner et al., 2012). As JNK-1 is a stress-associated kinase (Matsukawa et al., 2004), RIF treatment may activate a stress response through this cascade, involving its upstream kinase JKK-1, leading to the activation of DAF-16 that results in transcription of genes required for increased longevity. "
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    ABSTRACT: Advanced glycation end products (AGEs) are formed when glucose reacts nonenzymatically with proteins; these modifications are implicated in aging and pathogenesis of many age-related diseases including type II diabetes, atherosclerosis, and neurodegenerative disorders. Thus, pharmaceutical interventions that can reduce AGEs may delay age-onset diseases and extend lifespan. Using LC-MS(E) , we show that rifampicin (RIF) reduces glycation of important cellular proteins in vivo and consequently increases lifespan in Caenorhabditis elegans by up to 60%. RIF analog rifamycin SV (RSV) possesses similar properties, while rifaximin (RMN) lacks antiglycation activity and therefore fails to affect lifespan positively. The efficacy of RIF and RSV as potent antiglycating agents may be attributed to the presence of a p-dihydroxyl moiety that can potentially undergo spontaneous oxidation to yield highly reactive p-quinone structures, a feature absent in RMN. We also show that supplementing rifampicin late in adulthood is sufficient to increase lifespan. For its effect on longevity, rifampicin requires DAF-18 (nematode PTEN) as well as JNK-1 and activates DAF-16, the FOXO homolog. Interestingly, the drug treatment modulates transcription of a different subset of DAF-16 target genes, those not controlled by the conserved Insulin-IGF-1-like signaling pathway. RIF failed to increase the lifespan of daf-16 null mutant despite reducing glycation, showing thereby that DAF-16 may not directly affect AGE formation. Together, our data suggest that the dual ability to reduce glycation in vivo and activate prolongevity processes through DAF-16 makes RIF and RSV effective lifespan-extending interventions. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Full-text · Article · Feb 2015 · Aging cell
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    • "According to its positive regulation of apoptosis, a substantial body of evidence implicates JNK proteins in tumor suppression (Davis, 2000; Wagner and Nebreda, 2009). First, animal studies have demonstrated that JNK1-deficient mice are highly susceptible to tumor development (She et al., 2002; Tong et al., 2007), and more recently, impaired JNK signaling was shown to accelerate tumorigenesis in prostate, breast, or pancreatic cancer (Cellurale et al., 2012; Davies et al., 2014; Hü bner et al., 2012). Second, JNK can sensitize cancer cells to genotoxic stress-induced cell death (Sau et al., 2012; Song et al., 2012; Xiao et al., 2012), and knockdown of both JNK1 and JNK2 by small interfering RNA impaired apoptosis in response to anticancer drugs (Oleinik et al., 2007). "
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    ABSTRACT: The c-Jun N-terminal kinase (JNK) family, with its three members JNK1, JNK2, and JNK3, is a subfamily of mitogen-activated protein kinases. Involved in many aspects of cellular processes, JNK has been also associated with pathological states such as neurodegenerative diseases, inflammation, and cancers. In oncology, each isoform plays a distinct role depending on the context of the targeted tissue/organ, the tumor stage, and, most likely, the signaling pathway activated upstream. Consequently, the current challenge in finding new successful anti-JNK therapies is to design isoform-selective inhibitors of the JNKs. In this review, a particular focus is given to the JNK inhibitors that have been developed thus far when examining 3D structures of various JNK-inhibitor complexes. Using current data regarding structure-activity relationships and medicinal chemistry approaches, our objective is to provide a better understanding of the design and development of selective JNK inhibitors in the present and future. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Nov 2014 · Chemistry & biology
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    • "Initially, this was a counterintuitive observation due to the fact that this phosphosite has previously been described as an oncogene, and we have measured castration resistance in the cell lines inverse to the amount of p-JNK (Additional file 6: Figure S2) [25]. However, this observation corroborates recent work indicating that JNK acts as an oncogene in tumor development and a tumor suppressor in regards to castration resistant growth [19]. "
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    ABSTRACT: Background Although recent progress has been made in treating castration resistant prostate cancer, the interplay of signaling pathways which enable castration resistant growth is incompletely understood. A data driven, multivariate approach, was used in this study to predict prostate cancer cell survival based on the phosphorylation levels of key proteins in PC3, LNCaP, and MDA-PCa-2b cell lines in response to EGF, IGF1, IL6, TNFα, dihydrotestosterone, and docetaxel treatment. Methods The prostate cancer cell lines were treated with ligands or inhibitors, cell lyates were collected, and the amount of phosphoprotein quantified using 384 well ELISA assays. In separate experiments, relative cell viability was determined using an MTT assay. Normalized data was imported into Matlab where regression analysis was performed. Results Based on a linear model developed using partial least squares regression, p-Erk1/2 was found to correlate with castration resistant survival along with p-RPS6, and this model was determined to have a leave-one-out cross validated R2 value of 0.61. The effect of androgen on the phosphoproteome was examined, and increases in PI3K related phosphoproteins (p-Akt, p-RPS6, and p-GSK3) were observed which accounted for the majority of the significant increase in androgen-mediated cell survival. Simultaneous inhibition of the PI3K pathway and treatment with androgen resulted in a non-significant increase in survival. Given the strong effect of PI3K related signaling in enabling castration resistant survival, the specific effect of mTor versus complete inhibition was examined using targeted inhibitors. It was determine that mTor inhibition accounts for 52% of the effect of complete PI3K inhibition on cell survival. The differences in signaling between the cell lines were explored it was observed that MDA-PCa-2b exhibited far less activation of p-Erk in response to varying treatments, explaining one of the reasons for the lack of castration resistance. Conclusion In this work, regression analysis to the phosphoproteome was used to illustrate the sources of castration resistance between the cell lines including reduced p-Erk signaling in MDA-PCa-2b and variations in p-JNK across the cell lines, as well as studying the signaling pathways which androgen acts through, and determining the response to treatment with targeted inhibitors.
    Full-text · Article · May 2014 · BMC Cancer
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