The NF-κB/IκB signaling pathway is a critical regulator of cell survival in cancer. Here, we report that combined down-regulation of growth arrest- and DNA-damage-inducible proteins (GADD)45α and γ expression by NF-κB is an essential step for various cancer types to escape programmed cell death. We demonstrate that inhibition of NF-κB in cancer cells results in GADD45α- and γ-dependent induction of apoptosis and inhibition of tumor growth. Inhibition of GADD45α and γ in cancer cells by small interfering RNA abrogates apoptosis induction by the inhibitor of NF-κB and blocks c-Jun N-terminal kinase activation, whereas overexpression of GADD45α and γ activates c-Jun N-terminal kinase and induces apoptosis. These results establish an unambiguous role for the GADD45 family as an essential mediator of cell survival in cancer cells with implications for cancer chemotherapy and novel drug discovery.
BackgroundMind-body practices that elicit the relaxation response (RR) have been used worldwide for millennia to prevent and treat disease. The RR is characterized by decreased oxygen consumption, increased exhaled nitric oxide, and reduced psychological distress. It is believed to be the counterpart of the stress response that exhibits a distinct pattern of physiology and transcriptional profile. We hypothesized that RR elicitation results in characteristic gene expression changes that can be used to measure physiological responses elicited by the RR in an unbiased fashion.Methods/Principal FindingsWe assessed whole blood transcriptional profiles in 19 healthy, long-term practitioners of daily RR practice (group M), 19 healthy controls (group N1), and 20 N1 individuals who completed 8 weeks of RR training (group N2). 2209 genes were differentially expressed in group M relative to group N1 (p<0.05) and 1561 genes in group N2 compared to group N1 (p<0.05). Importantly, 433 (p<10−10) of 2209 and 1561 differentially expressed genes were shared among long-term (M) and short-term practitioners (N2). Gene ontology and gene set enrichment analyses revealed significant alterations in cellular metabolism, oxidative phosphorylation, generation of reactive oxygen species and response to oxidative stress in long-term and short-term practitioners of daily RR practice that may counteract cellular damage related to chronic psychological stress. A significant number of genes and pathways were confirmed in an independent validation set containing 5 N1 controls, 5 N2 short-term and 6 M long-term practitioners.Conclusions/SignificanceThis study provides the first compelling evidence that the RR elicits specific gene expression changes in short-term and long-term practitioners. Our results suggest consistent and constitutive changes in gene expression resulting from RR may relate to long term physiological effects. Our study may stimulate new investigations into applying transcriptional profiling for accurately measuring RR and stress related responses in multiple disease settings.
Conclusion. ESE-1 is expressed in synovial tissues in RA and, to a variable extent, in OA, and is specifically induced in synovial fibroblasts, chondroDr. Libermann
Deregulation of the receptor tyrosine kinase Axl has been implicated in the progression of several human cancers. However, the role of Axl in prostate cancer remains poorly understood, and the therapeutic efficacy of Axl targeting remains untested. In this report we identified Axl as a new therapeutic target for prostate cancer. Axl is consistently overexpressed in prostate cancer cell lines and human prostate tumors. Interestingly, the blockage of Axl gene expression strongly inhibits proliferation, migration, invasion, and tumor growth. Furthermore, inhibition of Axl expression by small interfering RNA regulates a transcriptional program of genes involved in cell survival, strikingly all connected to the NF-κB pathway. Additionally, blockage of Axl expression leads to inhibition of Akt, IKKα and IκBα phosphorylation, increasing IκBα expression and stability. Furthermore, induction of Akt phosphorylation by IGF1 in Axl knockdown cells restores Akt activity and proliferation. Taken together our results establish an unambiguous role for Axl in prostate cancer tumorigenesis with implications for prostate cancer treatment.
The receptor tyrosine kinase Axl has been implicated in the malignancy of different types of cancer. Emerging evidence of Axl upregulation in numerous cancers, as well as reports demonstrating that its inhibition blocks tumor formation in animal models, highlight the importance of Axl as a new potential therapeutic target. Furthermore, recent data demonstrate that Axl plays a pivotal role in resistance to chemotherapeutic regimens. In this review we discuss the functions of Axl and its regulation and role in cancer development, resistance to therapy, and its importance as a potential drug target, focusing on acute myeloid leukemia, breast, prostate and non-small cell lung cancers. Tyrosine KinasesTyrosine kinases (TKs), proteins that represent a major portion of all oncoproteins, are essential mediators of the signal transduction process and play essential roles in cell differentiation, migration, proliferation, apoptosis and metabolism. TKs are a class of enzymes which selectively catalyze phosphorylation of selected tyrosine residues in target proteins using ATP. This post-translational modification is a critical component for normal cellular communication and homeostasis and it is associated with several steps of development and progression of cancers.
The epithelium-specific Ets transcription factor, PDEF, plays a role in prostate and breast cancer, although its precise function has not been established. In prostate cancer, PDEF is involved in regulating prostate-specific antigen expression via interaction with the androgen receptor and NKX3.1, and down-regulation of PDEF by antiproliferative agents has been associated with reduced PDEF expression. We now report that reduced expression of PDEF leads to a morphologic change, increased migration and invasiveness in prostate cancer cells, reminiscent of transforming growth factor B (TGFB) function and epithelial-to-mesenchymal transition. Indeed, inhibition of PDEF expression triggers a transcriptional program of genes involved in the TGFB pathway, migration, invasion, adhesion, and epithelial dedifferentiation. Our results establish PDEF as a critical regulator of genes involved in cell motility, invasion, and adhesion of prostate cancer cells.
The growth arrest and DNA damage-inducible 45 (GADD45) gene product has been implicated in the stress response, cell cycle arrest, and apoptosis. Here we demonstrated the unexpected expression of GADD45 in the embryonic growth plate and uncovered its novel role as an essential mediator of matrix metalloproteinase-13 (MMP-13) expression during terminal chondrocyte differentiation. We identified GADD45 as a prominent early response gene induced by bone morphogenetic protein-2 (BMP-2) through a Smad1/Runx2-dependent pathway. Because this pathway is involved in skeletal development, we examined mouse embryonic growth plates, and we observed expression of Gadd45 mRNA coincident with Runx2 protein in pre-hypertrophic chondrocytes, whereas GADD45 protein was localized prominently in the nucleus in late stage hypertrophic chondrocytes where Mmp-13 mRNA was expressed. In Gadd45 ؊/؊ mouse embryos, defective mineralization and decreased bone growth accompanied deficient Mmp-13 and Col10a1 gene expression in the hypertrophic zone. Transduction of small interfering RNA-GADD45 in epiphyseal chondrocytes in vitro blocked terminal differentiation and the associated expression of Mmp-13 and Col10a1 mRNA in vitro. Finally, GADD45 stimulated MMP-13 promoter activity in chondrocytes through the JNK-mediated phosphorylation of JunD, partnered with Fra2, in synergy with Runx2. These observations indicated that GADD45 plays an essential role during chondrocyte terminal differentiation.Growth arrest and DNA damage-inducible (GADD) 4 45 is a member of the GADD45 family of small (18 kDa) proteins, also including GADD45␣ and GADD45␥. The GADD45 family is known to be associated with cell growth control, apoptotic cell death, and the cellular response to DNA damage (1, 2). Initially, GADD45, encoded by MyD118, was identified as a myeloid differentiation primary response gene activated by IL-6 in murine myeloid leukemia cells upon induction of terminal differentiation (1, 3). More recently, GADD45, which is induced by TGF- in a SMAD-dependent manner, has been identified as a positive regulator of TGF--induced apoptosis (4). Although GADD45␣ has been identified on DNA microarrays as prominently expressed genes in chondrocytes from adult articular cartilage and in chondrosarcoma or immortalized chondrocyte cell lines (5, 6), a role for GADD45 family members, including GADD45, during cartilage development has not been reported previously.Formation of the vertebrate skeleton through endochondrial ossification, involving progressive differentiation of proliferating chondrocytes to growth-arrested hypertrophic cells, is one of the most complex processes in biology. In the embryonic or postnatal growth plate, terminal chondrocyte differentiation occurs during conversion of cartilage to a vascularized tissue that supports matrix remodeling, cartilage calcification, and recruitment of osteogenic precursors. Cascades of growth and differentiation factors act through positive and negative signaling kinases and transcription factors to t...
Objective Our previous study suggested that growth arrest and DNA damage–inducible protein 45β (GADD45β) prolonged the survival of hypertrophic chondrocytes in the developing mouse embryo. This study was undertaken, therefore, to investigate whether GADD45β plays a role in adult articular cartilage. Methods Gene expression profiles of cartilage from patients with late-stage osteoarthritis (OA) were compared with those from patients with early OA and normal controls in 2 separate microarray analyses. Histologic features of cartilage were graded using the Mankin scale, and GADD45β was localized by immunohistochemistry. Human chondrocytes were transduced with small interfering RNA (siRNA)–GADD45β or GADD45β-FLAG. GADD45β and COL2A1 messenger RNA (mRNA) levels were analyzed by real-time reverse transcriptase–polymerase chain reaction, and promoter activities were analyzed by transient transfection. Cell death was detected by Hoechst 33342 staining of condensed chromatin. Results GADD45β was expressed at higher levels in cartilage from normal donors and patients with early OA than in cartilage from patients with late-stage OA. All chondrocyte nuclei in normal cartilage immunostained for GADD45β. In early OA cartilage, GADD45β was distributed variably in chondrocyte clusters, in middle and deep zone cells, and in osteophytes. In contrast, COL2A1, other collagen genes, and factors associated with skeletal development were up-regulated in late OA, compared with early OA or normal cartilage. In overexpression and knockdown experiments, GADD45β down-regulated COL2A1 mRNA and promoter activity. NF-κB overexpression increased GADD45β promoter activity, and siRNA-GADD45β decreased cell survival per se and enhanced tumor necrosis factor α–induced cell death in human articular chondrocytes. Conclusion These observations suggest that GADD45β might play an important role in regulating chondrocyte homeostasis by modulating collagen gene expression and promoting cell survival in normal adult cartilage and in early OA.
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