Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence

Demelash, Abeba; Pfannenstiel, Lukas W.; Liu, Li; Gastman, Brian

doi:10.18632/oncotarget.15962

Cited by 19 publications

(12 citation statements)

References 76 publications

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“…MCL-1 plays a role in suppressing the generation of reactive oxygen species (ROS). 29 Treatment with MS1/NPs had little, if any, effect on MCL-1 expression and was associated with the upregulation of MUC1-C, NF-κB p65 and BCL2A1 (Fig. 4b ), consistent with the finding that ROS activate the MUC1-C→NF-κB p65 pathway.…”

Section: Resultssupporting

confidence: 82%

Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer

Hiraki

Maeda

Mehrotra

et al. 2018

Sig Transduct Target Ther

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B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family of anti-apoptotic proteins that confers resistance to treatment with anti-cancer drugs; however, there are presently no agents that target BCL2A1. The MUC1-C oncoprotein is aberrantly expressed in triple-negative breast cancer (TNBC) cells, induces the epithelial–mesenchymal transition (EMT) and promotes anti-cancer drug resistance. The present study demonstrates that targeting MUC1-C genetically and pharmacologically in TNBC cells results in the downregulation of BCL2A1 expression. The results show that MUC1-C activates the BCL2A1 gene by an NF-κB p65-mediated mechanism, linking this pathway with the induction of EMT. The MCL-1 anti-apoptotic protein is also of importance for the survival of TNBC cells and is an attractive target for drug development. We found that inhibiting MCL-1 with the highly specific MS1 peptide results in the activation of the MUC1-C→NF-κB→BCL2A1 pathway. In addition, selection of TNBC cells for resistance to ABT-737, which inhibits BCL-2, BCL-xL and BCL-W but not MCL-1 or BCL2A1, is associated with the upregulation of MUC1-C and BCL2A1 expression. Targeting MUC1-C in ABT-737-resistant TNBC cells suppresses BCL2A1 and induces death, which is of potential therapeutic importance. These findings indicate that MUC1-C is a target for the treatment of TNBCs unresponsive to agents that inhibit anti-apoptotic members of the BCL-2 family.

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Section: Resultssupporting

confidence: 82%

Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer

Hiraki

Maeda

Mehrotra

et al. 2018

Sig Transduct Target Ther

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“…Bolesta et al 28 have shown that MCL1 localizes to mitochondria and prevents senescence and loss of phosphorylation of retinoblastoma (RB) protein, which is followed by inhibition of ROS production 29 . MCL1 is also involved in the downregulation of p27 expression, a critical inducer of senescence 29 , and decreases ROS production and senescence via NOX4 during chemotherapy 30 . This can be one possibility of downregulation of senescence and ROS in osteoarthritic chondrocytes in the present study.…”

Section: Discussionmentioning

confidence: 99%

RHEB gene therapy maintains the chondrogenic characteristics and protects cartilage tissue from degenerative damage during experimental murine osteoarthritis

Ashraf

Kim

Park

et al. 2019

Osteoarthritis and Cartilage

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Objective: Osteoarthritis (OA) is characterized by cartilage degeneration resulting from hypertrophic changes in chondrocytes caused by altered gene expression. The involvement of Ras homolog enriched in brain (RHEB) in OA regulation is unclear. Methods: Human knee articular cartilage samples-were analyzed for structural and biological changes by histology, immunohistochemistry, real time PCR and western blotting. OA-mouse model developed by surgical destabilization of the medial meniscus (DMM) were treated with adenovirus harboring Rheb gene to analyze onset and progression of OA. Histological scoring, immunohistochemistry, and TUNEL assay was performed to assess cartilage damage across the entire joint. Results: Human and mouse OA cartilage is degenerated and has markedly reduced levels of RHEB. Human OA-degenerated chondrocytes (DC) exhibited a fibroblastic phenotype and 80 % of degenerative cartilage were senescent, with higher levels of reactive oxygen species (ROS). Gene expression analysis of DC revealed almost no COL2A1 expression and reduced SOX9 and RHEB expression. Transient transfection of RHEB rescued the DC phenotype and reduced senescence and ROS levels markedly. RHEB overexpression also increased COL2A1 and SOX9 expression. In an OA-mouse model, the Rheb protein level decreased as the severity of OA increased. Ectopic expression of Rheb using adenovirus in mouse-OA cartilage suppressed surgically-induced OA pathogenesis accompanied by modulation of Adamts5, Mmp 13, Col 10, and Col2a1 expression. Rheb induction significantly reduced apoptosis in OA-cartilage. Conclusion: RHEB plays an important role in maintaining the chondrogenic characteristics of chondrocytes, and has potential in preventing progression of OA in the destabilize the medial meniscus (DMM) mouse model of OA.

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“…SGK1 can negatively regulate JNK signaling, an important inducer of superoxide species by modulating complex I activity of the electron transport chain ( 87 , 88 ). In addition, SGK1-mediated inactivation of GSK3-β facilitates MCL1 localization to the mitochondria to significantly reduce mitochondrial ROS production through inhibition of NOX4 expression, adversely affecting the response to chemotherapy ( 88 , 89 ). It is important to note, however, that in models of lung cancer, MCL1 may also promote ROS production from the mitochondria by binding to voltage-dependent anion channels and increasing the mitochondrial flux of calcium ( 90 ).…”

Section: Pi3k/akt Signaling Maintains Redox Balance In Cancer Cellsmentioning

confidence: 99%

Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer

2018

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Metabolic rewiring and the consequent production of reactive oxygen species (ROS) are necessary to promote tumorigenesis. At the nexus of these cellular processes is the aberrant regulation of oncogenic signaling cascades such as the phosphoinositide 3-kinase and AKT (PI3K/Akt) pathway, which is one of the most frequently dysregulated pathways in cancer. In this review, we examine the regulation of ROS metabolism in the context of PI3K-driven tumors with particular emphasis on four main areas of research. (1) Stimulation of ROS production through direct modulation of mitochondrial bioenergetics, activation of NADPH oxidases (NOXs), and metabolic byproducts associated with hyperactive PI3K/Akt signaling. (2) The induction of pro-tumorigenic signaling cascades by ROS as a consequence of phosphatase and tensin homolog and receptor tyrosine phosphatase redox-dependent inactivation. (3) The mechanisms through which PI3K/Akt activation confers a selective advantage to cancer cells by maintaining redox homeostasis. (4) Opportunities for therapeutically exploiting redox metabolism in PIK3CA mutant tumors and the potential for implementing novel combinatorial therapies to suppress tumor growth and overcome drug resistance. Further research focusing on the multi-faceted interactions between PI3K/Akt signaling and ROS metabolism will undoubtedly contribute to novel insights into the extensive pro-oncogenic effects of this pathway, and the identification of exploitable vulnerabilities for the treatment of hyperactive PI3K/Akt tumors.

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Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence

Cited by 19 publications

References 76 publications

Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer

Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer

RHEB gene therapy maintains the chondrogenic characteristics and protects cartilage tissue from degenerative damage during experimental murine osteoarthritis

Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer

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