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Title: Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells

Authors:
; ; ; ; ; ;
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1396512
Grant/Contract Number:
SE0012476
Resource Type:
Journal Article: Publisher's Accepted Manuscript
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 486; Journal Issue: 3; Related Information: CHORUS Timestamp: 2017-10-04 09:24:27; Journal ID: ISSN 0006-291X
Publisher:
Elsevier
Country of Publication:
United States
Language:
English

Citation Formats

McDonald, Elizabeth S., Mankoff, Julia, Makvandi, Mehran, Chu, Wenhua, Chu, Yunxiang, Mach, Robert H., and Zeng, Chenbo. Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells. United States: N. p., 2017. Web. doi:10.1016/j.bbrc.2017.03.122.
McDonald, Elizabeth S., Mankoff, Julia, Makvandi, Mehran, Chu, Wenhua, Chu, Yunxiang, Mach, Robert H., & Zeng, Chenbo. Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells. United States. doi:10.1016/j.bbrc.2017.03.122.
McDonald, Elizabeth S., Mankoff, Julia, Makvandi, Mehran, Chu, Wenhua, Chu, Yunxiang, Mach, Robert H., and Zeng, Chenbo. Mon . "Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells". United States. doi:10.1016/j.bbrc.2017.03.122.
@article{osti_1396512,
title = {Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells},
author = {McDonald, Elizabeth S. and Mankoff, Julia and Makvandi, Mehran and Chu, Wenhua and Chu, Yunxiang and Mach, Robert H. and Zeng, Chenbo},
abstractNote = {},
doi = {10.1016/j.bbrc.2017.03.122},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 486,
place = {United States},
year = {Mon May 01 00:00:00 EDT 2017},
month = {Mon May 01 00:00:00 EDT 2017}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.bbrc.2017.03.122

Citation Metrics:
Cited by: 1work
Citation information provided by
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  • Highlights: •Some clinical breast cancers are associated with MCU overexpression. •MCU silencing did not alter cell death initiated with the Bcl-2 inhibitor ABT-263. •MCU silencing potentiated caspase-independent cell death initiated by ionomycin. •MCU silencing promoted ionomycin-mediated cell death without changes in bulk Ca{sup 2+}. -- Abstract: The mitochondrial calcium uniporter (MCU) transports free ionic Ca{sup 2+} into the mitochondrial matrix. We assessed MCU expression in clinical breast cancer samples using microarray analysis and the consequences of MCU silencing in a breast cancer cell line. Our results indicate that estrogen receptor negative and basal-like breast cancers are characterized by elevated levelsmore » of MCU. Silencing of MCU expression in the basal-like MDA-MB-231 breast cancer cell line produced no change in proliferation or cell viability. However, distinct consequences of MCU silencing were seen on cell death pathways. Caspase-dependent cell death initiated by the Bcl-2 inhibitor ABT-263 was not altered by MCU silencing; whereas caspase-independent cell death induced by the calcium ionophore ionomycin was potentiated by MCU silencing. Measurement of cytosolic Ca{sup 2+} levels showed that the promotion of ionomycin-induced cell death by MCU silencing occurs independently of changes in bulk cytosolic Ca{sup 2+} levels. This study demonstrates that MCU overexpression is a feature of some breast cancers and that MCU overexpression may offer a survival advantage against some cell death pathways. MCU inhibitors may be a strategy to increase the effectiveness of therapies that act through the induction of caspase-independent cell death pathways in estrogen receptor negative and basal-like breast cancers.« less
  • Purpose: To identify the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) during {gamma}-ionizing radiation ({gamma}-IR) treatment for non-small-cell lung cancer cells. Methods and Materials: Wild-type PTEN or mutant forms of PTEN plasmids were transfected to construct stable transfectants of the NCI-H1299 non-small-cell lung cancer cell line. Combined effects of PTEN expression and IR treatment were tested using immunoblot, clonogenic, and cell-counting assays. Related signaling pathways were studied with immunoblot and kinase assays. Results: At steady state, stable transfectants showed almost the same proliferation rate but had different AKT phosphorylation patterns. When treated with {gamma}-IR, wild-type PTENmore » transfectants showed higher levels of cell death compared with mock vector or mutant transfectants, and showed increased G{sub 2}/M cell-cycle arrest accompanied by p21 induction and CDK1 inactivation. NCI-H1299 cells were treated with phosphosinositide-3 kinase (PI3K)/AKT pathway inhibitor (LY29002), resulting in reduced AKT phosphorylation levels. Treatment of NCI-H1299 cells with LY29002 and {gamma}-IR resulted in increased cell-cycle arrest and p21 induction. Endogenous wild-type PTEN-containing NCI-H460 cells were treated with PTEN-specific siRNA and then irradiated with {gamma}-IR: however reduced PTEN levels did not induce cell-cycle arrest or p21 expression. Conclusions: Taken together, these findings indicate that PTEN may modulate cell death or the cell cycle via AKT inactivation by PTEN and {gamma}-IR treatment. We also propose that a PTEN-PI3K/AKT-p21-CDK1 pathway could regulate cell death and the cell cycle by {gamma}-IR treatment.« less
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