p38α Mediates Cell Survival in Response to Oxidative Stress via Induction of Antioxidant Genes

Gutiérrez-Uzquiza, Álvaro; Arechederra, María; Bragado, Paloma; Aguirre‐Ghiso, Julio A.; Porrás, Almudena

doi:10.1074/jbc.m111.323709

Cited by 124 publications

(114 citation statements)

References 33 publications

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“…Treatment with GO-203, but not CP-2, was also associated with increased expression of ATF2 (supplemental Figure 2A-B), another transcription factor that is activated in the response to oxidative stress. 36 In addition and as found for CHOP, the GO-203/BTZ combination was highly effective in inducing ATF2 expression ( Figure 1E, left and right). These findings indicate that targeting MUC1-C promotes BTZ-mediated induction of oxidative stress.…”

supporting

confidence: 72%

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

Kufe

Avigan

et al. 2014

Blood

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• Targeting the MUC1-C oncoprotein in MM cells potentiates BTZ-induced downregulation of TIGAR and thereby ROS-mediated death.• Targeting MUC1-C is effective in resensitizing BTZ-resistant MM cells to BTZ and thus represents a potential strategy for combination treatment.The proteosome inhibitor bortezomib (BTZ) induces endoplasmic reticulum and oxidative stress in multiple myeloma (MM) cells. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in most MM cells, and targeting MUC1-C with GO-203, a cell-penetrating peptide inhibitor of MUC1-C homodimerization, is effective in inducing reactive oxygen species (ROS)-mediated MM cell death. The present results demonstrate that GO-203 and BTZ synergistically downregulate expression of the p53-inducible regulator of glycolysis and apoptosis (TIGAR), which promotes shunting of glucose-6-phosphate into the pentose phosphate pathway to generate reduced glutathione (GSH). In turn, GO-203 blocks BTZ-induced increases in GSH and results in synergistic increases in ROS and MM cell death. The results also demonstrate that GO-203 is effective against BTZ-resistant MM cells. We show that BTZ resistance is associated with BTZ-induced increases in TIGAR and GSH levels, and that GO-203 resensitizes BTZ-resistant cells to BTZ treatment by synergistically downregulating TIGAR and GSH. The GO-203/BTZ combination is thus highly effective in killing BTZ-resistant MM cells. These findings support a model in which targeting MUC1-C is synergistic with BTZ in suppressing TIGARmediated regulation of ROS levels and provide an experimental rationale for combining with BTZ in certain settings of BTZ resistance. (Blood. 2014;123(19):2997-3006) IntroductionMultiple myeloma (MM) is a clonal malignancy of plasma cells that is characterized in part by the abnormal synthesis and secretion of monoclonal immunoglobulins or light chains.1 Cellular homeostasis is dependent on the balanced regulation of protein synthesis and degradation, the latter of which is predominantly mediated by the ubiquitin-proteosome pathway.2 Bortezomib (BTZ) is a reversible inhibitor of the proteosome that is effective in inducing apoptosis of MM cells and is active in the treatment of this disease.1 BTZ has improved response rates of MM patients to induction therapy and is being used as consolidation after frontline treatment or transplantation. 1,3 However, intrinsic and acquired resistance to BTZ represent a challenge for the treatment of MM, which remains an incurable disease.1 BTZ has been shown to activate the unfolded protein response (UPR), a pathway induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and associated with increases in reactive oxygen species (ROS). 4,5 In this way, BTZ treatment of MM cells induces expression of CCAAT/enhancer binding protein-homologous protein (CHOP; GADD153), a key transcription factor that participates in cellular responses to ER and oxidative stress. [6][7][8] The mechanistic basis for BTZ activity has also been attributed...

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supporting

confidence: 72%

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

Kufe

Avigan

et al. 2014

Blood

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“…ROS are important mediators that regulate both cellular survival and cell death in response to different stimuli, such as starvation, ionizing radiation, senescence, or chemotherapeutic agents (45)(46)(47). In our study, tetrandrine treatment significantly induced intracellular ROS production, which has been suggested to be essential for both autophagy and apoptosis (Fig.…”

Section: Discussionmentioning

confidence: 54%

Autophagy-related Gene 7 (ATG7) and Reactive Oxygen Species/Extracellular Signal-regulated Kinase Regulate Tetrandrine-induced Autophagy in Human Hepatocellular Carcinoma

Gong

Chen

Yao

et al. 2012

Journal of Biological Chemistry

124

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Background: Tetrandrine exhibits antitumor effects and causes liver cancer apoptosis. Results: Tetrandrine induced hepatocellular carcinoma autophagy via ATG7 and ROS/ERK in vitro, in vivo, and in Caenorhabditis elegans muscle cells. Conclusion: Tetrandrine is a potent autophagy agonist. Significance: Tetrandrine may be a promising clinical chemotherapeutic agent for human hepatocellular carcinoma.

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“…Chromatin Immunoprecipitation (ChIP) Assay-ChIP assay was performed essentially as described previously (30). Briefly, 2 ϫ 10 6 cells were fixed in 1% formaldehyde for 15 min to cross-link DNA with associated proteins.…”

Section: Methodsmentioning

confidence: 99%

Transcriptional Regulation of Oncogenic Protein Kinase Cϵ (PKCϵ) by STAT1 and Sp1 Proteins

Wang

Gutiérrez-Uzquiza

Garg

et al. 2014

Journal of Biological Chemistry

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Background: PKC⑀, a kinase widely implicated in tumorigenesis and metastasis, is overexpressed in many cancers. Results: Transcription factors Sp1 and STAT1 control the expression of PKC⑀ in cancer cells. Conclusion: Up-regulation of PKC⑀ is mediated by dysregulated transcriptional mechanisms. Significance: Our results may have significant implications for the development of approaches to target PKC⑀ and its effectors in cancer therapeutics.

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p38α Mediates Cell Survival in Response to Oxidative Stress via Induction of Antioxidant Genes

Cited by 124 publications

References 33 publications

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

Autophagy-related Gene 7 (ATG7) and Reactive Oxygen Species/Extracellular Signal-regulated Kinase Regulate Tetrandrine-induced Autophagy in Human Hepatocellular Carcinoma

Transcriptional Regulation of Oncogenic Protein Kinase Cϵ (PKCϵ) by STAT1 and Sp1 Proteins

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