Antisense p53 transduction leads to overexpression of bcl-2 and dexamethasone resistance in multiple myeloma

Iyer, R.; Ding, Lie; Batchu, Ramesh B.; Naugler, S.; Shammas, Masood A.; Munshi, Nikhil C.

doi:10.1016/s0145-2126(02)00064-4

Cited by 16 publications

(14 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, activated GR directly regulates Bnip3 gene transcription via a GRE site within the Bnip3 promoter. Notwithstanding, earlier studies show that glucocorticoids can act indirectly to regulate expression of the Bcl-2 gene family by modulating NF-κB (Ramdas andHarmon, 1998, Dhandapani et al, 2005) and p53 transcriptional activity (Miyashita et al, 1994, Miyashita and Reed, 1995, Maiyar et al, 1997, Crochemore et al, 2002, Iyer et al, 2003. Bnip3 expression has similarly been shown to be attenuated following inhibition of NF-κB (Baetz et al, 2005), a gene that is glucocorticoid regulated (Webster and Cidlowski, 1999).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Sandau

Handa

2007

Neuroscience

View full text Add to dashboard Cite

Neonatal administration of the synthetic glucocorticoid, dexamethasone (DEX) retards brain growth, alters adult behaviors and induces cell death in the rat brain, thereby implicating glucocorticoids as developmentally neuroendangering compounds. Glucocorticoids also increase expression of proapoptotic Bcl-2 family members and exacerbate expression of hypoxic responsive genes. Bnip3 is a pro-apoptotic Bcl-2 family member that is upregulated in response to hypoxia. In these studies, we investigated the interactions of glucocorticoid receptor and hypoxia in the regulation of Bnip3 mRNA in cortical neurons. Using quantitative real time RT-PCR, we found that DEX treatment of postnatal day 4-6 rat pups caused a significant increase in Bnip3 mRNA expression compared to vehicle controls. A significant increase in Bnip3 mRNA was also measured in primary cortical neurons 72 hours after treatment with RU28362, a glucocorticoid receptor selective agonist. In primary cortical neurons, hypoxia increased Bnip3 mRNA expression and this was exacerbated with RU28362 treatment. To elucidate the mechanism of glucocorticoid and hypoxia mediated regulation of Bnip3 transcription, a Bnip3 promoter -luciferase reporter construct was utilized in primary cortical neurons. Upregulation of the Bnip3 promoter was mediated by a single glucocorticoid response element and a hypoxic response element. Bnip3 overexpression in primary cortical neurons significantly increased cell death, which is dependent on the Bnip3 transmembrane domain. However, despite the increased expression of Bnip3 following glucocorticoid and hypoxia treatment, corresponding decreases in cell survival were minimal. These studies identify a novel pathway in the developing cortex through which glucocorticoids may enhance a metabolic insult, such as hypoxia. KeywordsBcl-2; glucocorticoid receptor; dexamethasone; primary cortical neurons; postnatal; apoptosis Corticosterone, the endogenous glucocorticoid secreted by the rat adrenal gland, binds with high affinity to two different receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) (Reagan and McEwen, 1997). MR activation is associated with a neuroprotective phenotype (Almeida et al., 2000), whereas GR activation is implicated in the induction of an endangered neural phenotype (Sapolsky et al., 1986, Reagan andMcEwen, 1997). For example, in the adult, GR activation by the synthetic glucocorticoid Name and address of corresponding author: Robert J. Handa, Colorado State University, Department of Biomedical Sciences, W103 Anatomy, 1617 Campus Delivery, Fort Collins, CO 80523-1617, Phone: (970) Facsimile: (970) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process er...

show abstract

Section: Discussionmentioning

confidence: 99%

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Sandau

Handa

2007

Neuroscience

View full text Add to dashboard Cite

show abstract

“…p53 is also controlling the expression of Bcl-2 at the level of transcription as antisense inhibition of p53 is associated with overexpression of Bcl-2 (38), and transient transfection analysis revealed that wild-type p53 repressed the Bcl-2 full-length promoter (26). In MCF-7 CisR cells, the down-regulation of wild-type p53 protein expression is associated with increased levels of BCL-2 suggesting that both events are interconnected in the resistant cells.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Pathway Analysis Identifies Amphiregulin as a Key Factor for Cisplatin Resistance of Human Breast Cancer Cells

Eckstein

Servan

Girard

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The use of platinum complexes for the therapy of breast cancer is an emerging new treatment modality. To gain insight into the mechanisms underlying cisplatin resistance in breast cancer, we used estrogen receptor-positive MCF-7 cells as a model system. We generated cisplatin-resistant MCF-7 cells and determined the functional status of epidermal growth factor receptor (EGFR), MAPK, and AKT signaling pathways by phosphoreceptor tyrosine kinase and phospho-MAPK arrays. The cisplatinresistant MCF-7 cells are characterized by increased EGFR phosphorylation, high levels of AKT1 kinase activity, and ERK1 phosphorylation. In contrast, the JNK and p38 MAPK modules of the MAPK signaling pathway were inactive. These conditions were associated with inactivation of the p53 pathway and increased BCL-2 expression. We investigated the expression of genes encoding the ligands for the ERBB signaling cascade and found a selective up-regulation of amphiregulin expression, which occurred at later stages of cisplatin resistance development. Amphiregulin is a specific ligand of the EGFR (ERBB1) and a potent mitogen for epithelial cells. After exposure to cisplatin, the resistant MCF-7 cells secreted amphiregulin protein over extended periods of time, and knockdown of amphiregulin expression by specific short interfering RNA resulted in a nearly complete reversion of the resistant phenotype. To demonstrate the generality and importance of our findings, we examined amphiregulin expression and cisplatin resistance in a variety of human breast cancer cell lines and found a highly significant correlation. In contrast, amphiregulin levels did not significantly correlate with cisplatin resistance in a panel of lung cancer cell lines. We have thus identified a novel function of amphiregulin for cisplatin resistance in human breast cancer cells.The use of platinum complexes for the therapy of breast carcinomas is an emerging new treatment modality that has recently been introduced into the clinical setting (reviewed in Ref. 1). Breast cancer is a family of diseases that consists of major categories, including HER-2-positive breast cancer; "triple-negative" tumors that are ER 3 -negative, progesterone receptor-negative, and HER-2-negative; and hormonally sensitive breast cancers. The estrogen receptor-expressing (ER-positive) breast cancers are the most prevalent (2). For the therapy of HER2-overexpressing metastatic breast cancer, platinum complexes have been used in combination with paclitaxel and trastuzumab, a humanized monoclonal IgG 1 that binds the extracellular domain of the ERBB2 (HER-2/neu) receptor (3). For the treatment of HER-2-positive locally advanced breast cancer, a combination of docetaxel, cisplatin, and trastuzumab has been used as primary systemic therapy (4). Several ongoing phase II studies explore the use of platinum salts for the therapy of breast cancer, including "triple-negative" (ER-, progesterone receptor-, and HER-2-negative) breast carcinomas.Cisplatin enters the cells predominantly by passive diffusion, where ...

show abstract

“…The t(14;18) translocation is not present in myeloma cells. This indicates that other mechanisms such as hypomethylation of the Bcl-2 gene [47], constitutive activity of NF-κB which induces Bcl-2 transcription [48][49][50], or loss of the p53 tumor suppressor gene which inhibits Bcl-2 gene expression [51][52][53], may be involved. High expression of Bcl-2 in malignant cells of patients with acute myeloid leukemia and high-grade B cell lymphoma is associated with poor response to therapy [54,55].…”

Section: Role Of Bcl-2 In Myelomamentioning

confidence: 99%

New Treatment Strategies for Multiple Myeloma by Targeting BCL-2 and the Mevalonate Pathway

Donk

Bloem²,

Spek³

et al. 2006

CPD

View full text Add to dashboard Cite

Insight into the mechanisms of primary or acquired drug resistance of (hematological) malignancies is critical for the development of new treatment strategies. This review will focus on Bcl-2 and the mevalonate pathway as targets for reversal of drug resistance in multiple myeloma. The Bcl-2 protein is highly expressed in myeloma patients and in vitro studies have shown its role in the regulation of chemosensitivity, which makes Bcl-2 an attractive target for treatment. Statins are widely used for the treatment of hypercholesteremia. Several in vitro studies have shown that statins may also kill hematological malignant cells including myeloma cells. We found that lovastatin induced apoptosis in myeloma and lymphoma cells by inhibition of geranylgeranylation and subsequent down regulation of Mcl-1, probably the most important anti-apoptotic protein in myeloma. Phase 1 and 2 studies have been performed with Bcl-2 antisense oligonucleotides and high dose simvastatin in combination with chemotherapy in heavily pre-treated myeloma patients. Encouraging results from these studies may provide the framework for the future application of new treatment strategies for myeloma.

show abstract

Antisense p53 transduction leads to overexpression of bcl-2 and dexamethasone resistance in multiple myeloma

Cited by 16 publications

References 18 publications

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

Epidermal Growth Factor Receptor Pathway Analysis Identifies Amphiregulin as a Key Factor for Cisplatin Resistance of Human Breast Cancer Cells

New Treatment Strategies for Multiple Myeloma by Targeting BCL-2 and the Mevalonate Pathway

Contact Info

Product

Resources

About