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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    • "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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    Aging cell 02/2015; 14(3). DOI:10.1111/acel.12327 · 6.34 Impact Factor
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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.
    Chemistry & biology 11/2014; 21(11):1433-1443. DOI:10.1016/j.chembiol.2014.09.007 · 6.65 Impact Factor
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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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    BMC Cancer 05/2014; 14(1):325. DOI:10.1186/1471-2407-14-325 · 3.36 Impact Factor
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