Adaptation to Oxidative Stress, Chemoresistance, and Cell Survival

Landriscina, Matteo; Maddalena, Francesca; Laudiero, Gabriella; Esposito, Franca

doi:10.1089/ars.2009.2692

Cited by 191 publications

(140 citation statements)

References 161 publications

Supporting

Mentioning

135

Contrasting

Order By: Relevance

“…Consistently, gene set enrichment analysis (GSEA) revealed that STEAP1 silencing regulates gene sets involved in oxidative stress responses, type II conjugation, and proteolysis (Supplementary Table S3), which are part of the oxidative stress phenotype seen in cancer (32,33).…”

Section: Knockdown Of Steap1 Inhibits Proliferation Invasion Anchormentioning

confidence: 70%

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

Grünewald

Diebold

Espósito

et al. 2012

Molecular Cancer Research

115

132

View full text Add to dashboard Cite

Ewing tumors comprise the second most common type of bone-associated cancer in children and are characterized by oncogenic EWS/FLI1 fusion proteins and early metastasis. Compelling evidence suggests that elevated levels of intracellular oxidative stress contribute to enhanced aggressiveness of numerous cancers, possibly including Ewing tumors. Using comprehensive microarray analyses and RNA interference, we identified the six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-a membrane-bound mesenchymal stem cell marker of unknown function-as a highly expressed protein in Ewing tumors compared with benign tissues and show its regulation by EWS/FLI1. In addition, we show that STEAP1 knockdown reduces Ewing tumor proliferation, anchorage-independent colony formation as well as invasion in vitro and decreases growth and metastasis of Ewing tumor xenografts in vivo. Moreover, transcriptome and proteome analyses as well as functional studies revealed that STEAP1 expression correlates with oxidative stress responses and elevated levels of reactive oxygen species that in turn are able to regulate redox-sensitive and proinvasive genes. In synopsis, our data suggest that STEAP1 is associated with the invasive behavior and oxidative stress phenotype of Ewing tumors and point to a hitherto unanticipated oncogenic function of STEAP1. Mol Cancer Res; 10(1); 52-65. Ó2011 AACR.

show abstract

Section: Knockdown Of Steap1 Inhibits Proliferation Invasion Anchormentioning

confidence: 70%

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

Grünewald

Diebold

Espósito

et al. 2012

Molecular Cancer Research

115

132

View full text Add to dashboard Cite

show abstract

“…41 Increased CuZnSOD expression was shown to induce imexon-resistance in myeloma cells. 42 TrxR1 expression and activity is increased in adriamycin-resistant leukemia cells and cisplatin-resistant ovarian cancer cells, and its inhibition using auranofin induced apoptosis in these cells.…”

Section: Discussionmentioning

confidence: 99%

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

et al. 2016

View full text Add to dashboard Cite

Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxicmyeloma cells to bortezomib. Hypoxia increased NF-kb subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-kb p65 protein levels in the nucleus and reduced the expression of NF-kb-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the na€ ıve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-kb-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-kb signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomibresistance and improve survival outcomes of MM patients.

show abstract

“…This may be particularly relevant as reactive oxygen species are primarily generated at complex I of the ETC, with CcO not normally directly involved in reactive oxygen species generation. This mechanism could be a part of a previously unrecognized adaptive chemoresistance mechanism linking both oxidative stress and drug resistance in cancer leading to suppressed apoptotic signaling (67).…”

Section: Discussionmentioning

confidence: 99%

Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Oliva

Nozell

Diers

et al. 2010

Journal of Biological Chemistry

167

199

View full text Add to dashboard Cite

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of high-grade gliomas. Acquired chemoresistance is a severe limitation to this therapy with more than 90% of recurrent gliomas showing no response to a second cycle of chemotherapy. Efforts to better understand the underlying mechanisms of acquired chemoresistance to TMZ and potential strategies to overcome chemoresistance are, therefore, critically needed. TMZ methylates nuclear DNA and induces cell death; however, the impact on mitochondria DNA (mtDNA) and mitochondrial bioenergetics is not known. Herein, we tested the hypothesis that TMZ-mediated alterations in mtDNA and respiratory function contribute to TMZ-dependent acquired chemoresistance. Using an in vitro model of TMZ-mediated acquired chemoresistance, we report 1) a decrease in mtDNA copy number and the presence of large heteroplasmic mtDNA deletions in TMZ-resistant glioma cells, 2) remodeling of the entire electron transport chain with significant decreases of complexes I and V and increases of complexes II/III and IV, and 3) pharmacologic and genetic manipulation of cytochrome c oxidase, which restores sensitivity to TMZ-dependent apoptosis in resistant glioma cells. Importantly, human primary and recurrent pairs of glioblastoma multiforme (GBM) biopsies as well as primary and TMZ-resistant GBM xenograft lines exhibit similar remodeling of the ETC. Overall these results suggest that TMZ-dependent acquired chemoresistance may be due to a mitochondrial adaptive response to TMZ genotoxic stress with a major contribution from cytochrome c oxidase. Thus, abrogation of this adaptive response may reverse chemoresistance and restore sensitivity to TMZ, providing a strategy for improved therapeutic outcomes in GBM patients.

show abstract

Adaptation to Oxidative Stress, Chemoresistance, and Cell Survival

Cited by 191 publications

References 161 publications

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Contact Info

Product

Resources

About