Diphenylene iodonium interferes with cell cycle progression and induces apoptosis by modulating NAD(P)H oxidase/ROS/cell cycle regulatory pathways in Burkitt’s lymphoma cells

Ding, Ya; Zhu, Wenjun; Sun, Rui; Yuan, Gang; Zhang, Dongsheng; Fan, Yuhua; Sun, Jian

doi:10.3892/or.2015.3726

Cited by 11 publications

(11 citation statements)

References 41 publications

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“…The NOX family has been suggested as potential therapeutic targets in prostate and pancreatic cancers, as well as Burkitt's lymphoma, melanomas, glioblastomas and TKI-sensitive CML [ 33 – 36 , 49 – 52 ]. Of the seven NOX complex family members, NOX1, NOX2, NOX4, NOX5, and DUOX2 have all been identified as isoforms present in CML [ 27 , 33 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies

et al. 2015

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Tyrosine kinase inhibitors (TKI) have improved CML response rates, and some are effective against resistance-promoting point mutations in BCR-ABL1. However, in the absence of point mutations, resistance still occurs. Here, we identify a novel pathway mediating resistance which connects p47phox, the organizer subunit of NADPH oxidase-2 (NOX2), with early growth response-1 (Egr-1) and the Src family kinase Fyn. We found up-regulation of p47phox, Egr-1, and Fyn mRNA and protein using paired isogenic CML cell lines and mined data. Isolation of CD34+ cells and tissue microarray staining from blast crisis CML patients confirmed in vivo over-expression of components of this pathway. Knockdown studies revealed that p47phox modulated reactive oxygen species and Egr-1 expression, which, in turn, controlled Fyn expression. Interestingly, Fyn knockdown sensitized TKI-resistant cells to dasatinib, a dual BCR-ABL1/Src inhibitor. Egr-1 knockdown had similar effects, indicating the utility of targeting Fyn expression over activation. Pointedly, p47phox knockdown also restored TKI-sensitivity, indicating that targeting the NOX2 complex can overcome resistance. The NOX2/Egr-1/Fyn pathway was also conserved within TKI-resistant EGFRΔIII-expressing glioblastoma and patient-derived glioblastoma stem cells. Thus, our findings suggest that targeting the NOX2/Egr-1/Fyn pathway may have clinical implications within multiple cancer types; particularly where efficacy of TKI is compromised.

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Section: Discussionmentioning

confidence: 99%

A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies

et al. 2015

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“…It was reported that the mitotic CDK14/cyclin Y complex promotes Wnt signaling (26). Moreover, Cdc25 is known to be involved cell cycle regulation (27). Caspase recruitment domain 6 (CARD6), a microtubule-interacting protein, belongs to the CARD family (28).…”

Section: Discussionmentioning

confidence: 99%

Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro

et al. 2015

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Lung cancer is the most common cause of cancer mortality and new cases are on the increase worldwide. However, the treatment of lung cancer remains unsatisfactory. Curcumin has been shown to induce cell death in many human cancer cells, including human lung cancer cells. However, the effects of curcumin on genetic mechanisms associated with these actions remain unclear. Curcumin (2 µM) was added to NCI-H460 human lung cancer cells and the cells were incubated for 24 h. Total RNA was extracted from isolated cells for cDNA synthesis, labeling, microarray hybridization and flour‑labeled cDNA hybridized on chip. Localized concentrations of fluorescent molecules were detected and quantified using Expression Console software (Affymetrix) with default RMA parameters. GeneGo software was used for the key genes involved and their possible interaction pathways. The results showed that ~170 genes were significantly upregulated and 577 genes were significantly downregulated in curcumin‑treated cells. Specifically, the up‑ and downregulated genes included CCNE2, associated with DNA damage; ID3, associated with cell survival and 146 genes with a >2- to 3-fold change including the TP53INP1 gene, associated with DNA damage; CDC6, CDCA5, TAKMIP2, CDK14, CDK5, CDCA76, CDC25A, CDC5L and SKP2, associated with cell cycle; the CARD6, ID1 and ID2 genes, associated with cell survival and the BRMS1L, associated with cell migration and invasion. Additionally, 59 downregulated genes exhibited a >4-fold change, including the DDIT3 gene, associated with DNA damage; while 97 genes had a >3- to 4-fold change including the DDIT4 gene, associated with DNA damage; the CCPG1 gene, associated with cell cycle and 321 genes with a >2- to 3-fold including the GADD45A and CGREF1 genes, associated with DNA damage; the CCPG1 gene, associated with cell cycle, the TNFRSF10B, GAS5, TSSC1 and TNFRSF11B gene, associated with cell survival and the ARHAP29 and CADM2 genes, associated with cell migration and invasion. In conclusion, gene alterations provide information regarding the cytotoxic mechanism of curcumin at the genetic level and provide additional biomarkers or targets for the treatment of human lung cancer.

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“…Recently, several studies including our reports have shown that EBV-infected cells have high ROS levels that are modulated by various mechanisms [28], [29]. However, it is still not known whether Nrf2 is activated in EBV-infected cells and how Nrf2 activation is related to expression of EBV-related proteins.…”

Section: Introductionmentioning

confidence: 94%

LMP1 and 2A Induce the Expression of Nrf2 Through Akt Signaling Pathway in Epstein-Barr Virus–Transformed B Cells

Yun

Kim

Hur

2019

Translational Oncology

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The transcription factor Nrf2, which regulates the expression of antioxidant and cytoprotective enzymes, contributes to cell proliferation and resistance to chemotherapy. Nrf2 is also dysregulated in many cancers such as lung, head and neck, and breast cancers, but its role in Epstein-Barr virus (EBV)–transformed B cells is still not understood. Here, we investigated EBV infection-induced Nrf2 activation in B cells by analyzing translocation of Nrf2 from the cytosol to the nucleus. In addition, we confirmed expression of the target genes in response to increased Nrf2 activation in EBV-transformed B cells. We demonstrated that knockdown of LMP1 and 2A blocks the translocation of Nrf2 to the nucleus and reduces ROS production in EBV-transformed B cells. Further, we showed that inhibition of Akt prevents Nrf2 activation. Moreover, knockdown of Nrf2 induces apoptotic cell death in EBV-transformed B cells. In conclusion, our study demonstrates that Nrf2 promotes proliferation of EBV-transformed B cells through the EBV-related proteins LMP1 and 2A and Akt signaling, implicating Nrf2 as a potential molecular target for EBV-associated disease.

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Diphenylene iodonium interferes with cell cycle progression and induces apoptosis by modulating NAD(P)H oxidase/ROS/cell cycle regulatory pathways in Burkitt’s lymphoma cells

Cited by 11 publications

References 41 publications

A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies

A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies

Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro

LMP1 and 2A Induce the Expression of Nrf2 Through Akt Signaling Pathway in Epstein-Barr Virus–Transformed B Cells

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