C/EBPβ regulates metastatic gene expression and confers TNF‐α resistance to prostate cancer cells

Kim, M. H.; Minton, Alena Z.; Agrawal, Vikas

doi:10.1002/pros.20993

Cited by 27 publications

(14 citation statements)

References 47 publications

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“…Prostate cancer cells commonly express three anti-apoptotic Bcl proteins: BCL-XL, BCL-2, and MCL-1 [28], [29]. Analysis of anti-apoptotic Bcl2 family protein expression levels in C42Luc cells treated with pro-apoptotic agents showed that MCL-1 expression is substantially decreased in cells treated with cycloheximide for 6 hours, and in cells treated with the combination of ZSTK474 and cycloheximide (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

BAD Dephosphorylation and Decreased Expression of MCL-1 Induce Rapid Apoptosis in Prostate Cancer Cells

et al. 2013

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PTEN loss and constitutive activation of the PI3K signaling pathway have been associated with advanced androgen-independent prostate cancer. PTEN-deficient prostate cancer C42Luc cells survive in serum-free media and show relative resistance to apoptosis even in the presence of the PI3K inhibitor ZSTK474. Yet, when ZSTK474 is combined with the translation inhibitor cycloheximide, C42Luc cells undergo apoptosis within 6 hours. We identified dephosphorylation of BAD (Bcl2-associated death promoter) as a main apoptosis-regulatory molecule downstream from PI3K, and loss of MCL-1 (Myeloid cell leukemia -1) as a major target of cycloheximide. The combination of MCL-1 knockdown and expression of phosphorylation-deficient mutant BAD2SA is sufficient to trigger rapid apoptosis in prostate cancer cells. These results establish the mechanism for the synergistic induction of apoptosis by the combination of a PI3K inhibitor and of a protein synthesis inhibitor in PTEN-deficient prostate cancer cells.

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Section: Resultsmentioning

confidence: 99%

BAD Dephosphorylation and Decreased Expression of MCL-1 Induce Rapid Apoptosis in Prostate Cancer Cells

et al. 2013

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“…Recent studies indicate that C/EBP-β is a master regulator of mesenchymal transformation and aggressive phenotype of human glioma cells [49]. In addition, C/EBP-β activates a variety of pro-survival and pro-metastatic genes, enhancing resistance to apoptosis in multiple myeloma and prostate carcinoma cells [50], [51]. Furthermore, C/EBP-β regulates energy balance, and promotes growth of colon cancer cells in part via activation of IGF-1, insulin, and leptin [52].…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Induces C/EBP-β-Mediated Activation of miR-31 in Normal Human Respiratory Epithelia and Lung Cancer Cells

et al. 2010

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BackgroundLimited information is available regarding mechanisms by which miRNAs contribute to pulmonary carcinogenesis. The present study was undertaken to examine expression and function of miRNAs induced by cigarette smoke condensate (CSC) in normal human respiratory epithelia and lung cancer cells.MethodologyMicro-array and quantitative RT-PCR (qRT-PCR) techniques were used to assess miRNA and host gene expression in cultured cells, and surgical specimens. Software-guided analysis, RNA cross-link immunoprecipitation (CLIP), 3′ UTR luciferase reporter assays, qRT-PCR, focused super-arrays and western blot techniques were used to identify and confirm targets of miR-31. Chromatin immunoprecipitation (ChIP) techniques were used to evaluate histone marks and transcription factors within the LOC554202 promoter. Cell count and xenograft experiments were used to assess effects of miR-31 on proliferation and tumorigenicity of lung cancer cells.ResultsCSC significantly increased miR-31 expression and activated LOC554202 in normal respiratory epithelia and lung cancer cells; miR-31 and LOC554202 expression persisted following discontinuation of CSC exposure. miR-31 and LOC554202 expression levels were significantly elevated in lung cancer specimens relative to adjacent normal lung tissues. CLIP and reporter assays demonstrated direct interaction of miR-31 with Dickkopf-1 (Dkk-1) and DACT-3. Over-expression of miR-31 markedly diminished Dkk-1 and DACT3 expression levels in normal respiratory epithelia and lung cancer cells. Knock-down of miR-31 increased Dkk-1 and DACT3 levels, and abrogated CSC-mediated decreases in Dkk-1 and DACT-3 expression. Furthermore, over-expression of miR-31 diminished SFRP1, SFRP4, and WIF-1, and increased Wnt-5a expression. CSC increased H3K4Me3, H3K9/14Ac and C/EBP-β levels within the LOC554202 promoter. Knock-down of C/EBP-β abrogated CSC-mediated activation of LOC554202. Over-expression of miR-31 significantly enhanced proliferation and tumorigenicity of lung cancer cells; knock-down of miR-31 inhibited growth of these cells.ConclusionsCigarette smoke induces expression of miR-31 targeting several antagonists of cancer stem cell signaling in normal respiratory epithelia and lung cancer cells. miR-31 functions as an oncomir during human pulmonary carcinogenesis.

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“…Increased expression of C/EBP␤ has been demonstrated in tumors of the colon, kidney, stomach, prostate, and the ovaries (6,(17)(18)(19). In many cases, high C/EBP␤ expression correlates with increased malignancy and invasiveness of the tumor cells.…”

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confidence: 99%

Helenalin Acetate, a Natural Sesquiterpene Lactone with Anti-inflammatory and Anti-cancer Activity, Disrupts the Cooperation of CCAAT Box/Enhancer-binding Protein β (C/EBPβ) and Co-activator p300

Jakobs

Steinmann

Henrich

et al. 2016

Journal of Biological Chemistry

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Edited by Joel GottesfeldRecent work has demonstrated pro-oncogenic functions of the transcription factor CCAAT box/enhancer-binding protein ␤ (C/EBP␤) in various tumors, implicating C/EBP␤ as an interesting target for the development of small-molecule inhibitors. We have previously discovered that the sesquiterpene lactone helenalin acetate, a natural compound known to inhibit NF-B, is a potent C/EBP␤ inhibitor. We have now examined the inhibitory mechanism of helenalin acetate in more detail. We demonstrate that helenalin acetate is a significantly more potent inhibitor of C/EBP␤ than of NF-B. Our work shows that helenalin acetate inhibits C/EBP␤ by binding to the N-terminal part of C/EBP␤, thereby disrupting the cooperation of C/EBP␤ with the co-activator p300. C/EBP␤ is expressed in several isoforms from alternative translational start codons. We have previously demonstrated that helenalin acetate selectively inhibits only the full-length (liver-enriched activating protein* (LAP*)) isoform but not the slightly shorter (LAP) isoform. Consistent with this, helenalin acetate binds to the LAP* but not to the LAP isoform, explaining why its inhibitory activity is selective for LAP*. Although helenalin acetate contains reactive groups that are able to interact covalently with cysteine residues, as exemplified by its effect on NF-B, the inhibition of C/EBP␤ by helenalin acetate is not due to irreversible reaction with cysteine residues of C/EBP␤. In summary, helenalin acetate is the first highly active small-molecule C/EBP␤ inhibitor that inhibits C/EBP␤ by a direct binding mechanism. Its selectivity for the LAP* isoform also makes helenalin acetate an interesting tool to dissect the functions of the LAP* and LAP isoforms.

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C/EBPβ regulates metastatic gene expression and confers TNF‐α resistance to prostate cancer cells

Abstract: Our study, for the first time, demonstrated that C/EBPbeta regulated cell growth and conferred TNF-alpha resistance to PCa cells, in part, via regulation of metastatic gene expression. Prostate 69: 1435-1447, 2009. (c) 2009 Wiley-Liss, Inc.

Cited by 27 publications

References 47 publications

BAD Dephosphorylation and Decreased Expression of MCL-1 Induce Rapid Apoptosis in Prostate Cancer Cells

BAD Dephosphorylation and Decreased Expression of MCL-1 Induce Rapid Apoptosis in Prostate Cancer Cells

Cigarette Smoke Induces C/EBP-β-Mediated Activation of miR-31 in Normal Human Respiratory Epithelia and Lung Cancer Cells

Helenalin Acetate, a Natural Sesquiterpene Lactone with Anti-inflammatory and Anti-cancer Activity, Disrupts the Cooperation of CCAAT Box/Enhancer-binding Protein β (C/EBPβ) and Co-activator p300

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