Suppression of RelB-mediated manganese superoxide dismutase expression reveals a primary mechanism for radiosensitization effect of 1α,25-dihydroxyvitamin D3 in prostate cancer cells

Xu, Yong; Fang, Fang; Clair, Daret K. St.; Josson, Sajni; Sompol, Pradoldej; Spasojević, Ivan; Clair, William H. St.

doi:10.1158/1535-7163.mct-06-0700

Cited by 58 publications

(52 citation statements)

References 50 publications

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“…Interestingly, activation of the dapk1, dapk3, c-flip, and birc3 promoters by RelB can be prevented by Daxx, which interacts selectively with RelB but not with RelA or c-Rel (36). In addition to the BCL2 gene (56), RelB induces transcription of several other prosurvival genes, including MNSOD in prostate cancer (60) and MNSOD and SURVIVIN in breast cancer (29). However, RelB was unable to bind to the NF-B elements upstream of shRNA (upper panels), or EV or full-length Bcl-2 (bottom panels).…”

Section: Discussionmentioning

confidence: 99%

RelB NF-κB Represses Estrogen Receptor α Expression via Induction of the Zinc Finger Protein Blimp1

Wang¹,

Belguise²,

O’Neill³

et al. 2009

Molecular and Cellular Biology

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Aberrant constitutive expression of NF-B subunits, reported in more than 90% of breast cancers and multiple other malignancies, plays pivotal roles in tumorigenesis. Higher RelB subunit expression was demonstrated in estrogen receptor alpha (ER␣)-negative breast cancers versus ER␣-positive ones, due in part to repression of RelB synthesis by ER␣ signaling. Notably, RelB promoted a more invasive phenotype in ER␣-negative cancers via induction of the BCL2 gene. We report here that RelB reciprocally inhibits ER␣ synthesis in breast cancer cells, which contributes to a more migratory phenotype. Specifically, RelB is shown for the first time to induce expression of the zinc finger repressor protein Blimp1 (B-lymphocyte-induced maturation protein), the critical mediator of Band T-cell development, which is transcribed from the PRDM1 gene. Blimp1 protein repressed ER␣ (ESR1) gene transcription. Commensurately higher Blimp1/PRDM1 expression was detected in ER␣-negative breast cancer cells and primary breast tumors. Induction of PRDM1 gene expression was mediated by interaction of Bcl-2, localized in the mitochondria, with Ras. Thus, the induction of Blimp1 represents a novel mechanism whereby the RelB NF-B subunit mediates repression, specifically of ER␣, thereby promoting a more migratory phenotype.NF-B is a structurally and evolutionary conserved family of dimeric transcription factors with subunits having an N-terminal region of approximately 300 amino acids that shares homology with the v-Rel oncoprotein (17, 44). The conserved Rel homology domain is responsible for DNA binding, dimerization, nuclear translocation, and interaction with inhibitory proteins of NF-B (IBs). Mammals express five NF-B members, including c-Rel, RelB, RelA (p65), p50, and p52, which can form either homo-or heterodimers. RelB differs from the other members in that it only binds DNA as a heterodimer with either p52 or p50 and interacts only poorly with the inhibitory protein IB␣. In most untransformed cells, other than B lymphocytes, NF-B complexes are sequestered in the cytoplasm bound to specific IB proteins.

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Section: Discussionmentioning

confidence: 99%

RelB NF-κB Represses Estrogen Receptor α Expression via Induction of the Zinc Finger Protein Blimp1

Wang¹,

Belguise²,

O’Neill³

et al. 2009

Molecular and Cellular Biology

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“…Genes related to cell cycle and apoptosis pathways such as ATM, CDKN1A, CDKN1B, CDKN2B and RB1 were severely compromised, as well as genes involved in acute leukemia pathway such as PPARD, STAT3, PBK, RELB and TP53BP1 already known to influence tumor susceptibility. [38][39][40] In particular, STAT3 is persistently activated in many human cancers and enhances transformation or blocks apoptosis in cell cultures. TP53BP1 is a key transducer of the DNA damage checkpoint signal; PBK has recently been demonstrated to be involved in leukemic growth arrest.…”

Section: Discussionmentioning

confidence: 99%

ICER expression inhibits leukemia phenotype and controls tumor progression

et al. 2008

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The inducible cyclic AMP (cAMP) early repressor (ICER) and cAMP response element-binding protein (CREB) are transcriptional regulators of the cAMP-mediated signaling pathway. CREB has been demonstrated to be upregulated in the majority of childhood leukemias contributing to disease progression, whereas ICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed in cell lines decreases CREB protein level and induces a lowered clonogenic potential in vitro. It decreases the ability of HL60 to invade the extramedullary sites and to promote bone marrow angiogenesis in nonobese diabetic-severe combined immunodeficient mice, demonstrating its potential effects on tumor progression. ICER represses the majority of 96 target genes upregulated by CREB. It binds CRE promoters and controls gene expression restoring the normal regulation of major cellular pathways. ICER is subjected to degradation through a constitutively active form of the extracellular signal-regulated protein kinase, which drives it to the proteasome. We propose that ICER is downregulated in HL60 to preserve CREB overexpression, which disrupts normal myelopoiesis and promotes blast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.

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“…NFkB also provides an adaptive response to PCa cells against cytotoxicity induced by redox-active therapeutic agents and is implicated in radiation resistance of cancers (Kimura et al 1999, Criswell et al 2003. Calcitriol significantly enhances the sensitivity of PCa cells to ionizing radiation by selectively suppressing radiation-mediated RelB activation (Xu et al 2007). Thus, calcitriol may serve as an effective agent for sensitizing PCa cells to radiation therapy via suppression of the NFkB pathway.…”

Section: Induction Of Mkp5 and Inhibition Of Stress-activated Kinase mentioning

confidence: 99%

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment

Krishnan¹,

Feldman²

2010

Endocrine-Related Cancer

129

118

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Calcitriol, the hormonally active form of vitamin D, exerts multiple anti-proliferative and pro-differentiating actions including cell cycle arrest and induction of apoptosis in many malignant cells, and the hormone is currently being evaluated in clinical trials as an anti-cancer agent. Recent research reveals that calcitriol also exhibits multiple anti-inflammatory effects. First, calcitriol inhibits the synthesis and biological actions of pro-inflammatory prostaglandins (PGs) by three mechanisms: i) suppression of the expression of cyclooxygenase-2, the enzyme that synthesizes PGs; ii) up-regulation of the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme that inactivates PGs; and iii) down-regulation of the expression of PG receptors that are essential for PG signaling. The combination of calcitriol and nonsteroidal anti-inflammatory drugs results in a synergistic inhibition of the growth of prostate cancer (PCa) cells and offers a potential therapeutic strategy for PCa. Second, calcitriol increases the expression of mitogenactivated protein kinase phosphatase 5 in prostate cells resulting in the subsequent inhibition of p38 stress kinase signaling and the attenuation of the production of pro-inflammatory cytokines. Third, calcitriol also exerts anti-inflammatory activity in PCa through the inhibition of nuclear factor-kB signaling that results in potent anti-inflammatory and anti-angiogenic effects. Other important direct effects of calcitriol as well as the consequences of its anti-inflammatory effects include the inhibition of tumor angiogenesis, invasion, and metastasis. We hypothesize that these anti-inflammatory actions, in addition to the other known anti-cancer effects of calcitriol, play an important role in its potential use as a therapeutic agent for PCa. Calcitriol or its analogs may have utility as chemopreventive agents and should be evaluated in clinical trials in PCa patients with early or precancerous disease.

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Suppression of RelB-mediated manganese superoxide dismutase expression reveals a primary mechanism for radiosensitization effect of 1α,25-dihydroxyvitamin D3 in prostate cancer cells

Cited by 58 publications

References 50 publications

RelB NF-κB Represses Estrogen Receptor α Expression via Induction of the Zinc Finger Protein Blimp1

RelB NF-κB Represses Estrogen Receptor α Expression via Induction of the Zinc Finger Protein Blimp1

ICER expression inhibits leukemia phenotype and controls tumor progression

Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment

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