<i>RNAi</i>-Mediated Silencing of Nuclear Factor Erythroid-2–Related Factor 2 Gene Expression in Non–Small Cell Lung Cancer Inhibits Tumor Growth and Increases Efficacy of Chemotherapy

Singh, Anju; Boldin-Adamsky, Swetlana; Thimmulappa, Rajesh K.; Rath, Srikanta Kumar; Ashush, Hagit; Coulter, Jonathan B.; Blackford, Amanda L.; Goodman, Steven N.; Bunz, Fred; Watson, Walter H.; Gabrielson, Edward; Feinstein, Elena; Biswal, Shyam

doi:10.1158/0008-5472.can-08-1401

Cited by 348 publications

(351 citation statements)

References 47 publications

Supporting

Mentioning

321

Contrasting

Unclassified

Order By: Relevance

“…Recently an exciting report by Singh et al showed that siRNA-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibited tumor growth and increased efficacy of chemotherapy (Singh et al, 2008). Therefore, identification and silencing of genes related to the growth and survival of lung cancer cells would be an interesting area of research.…”

Section: Silencing Of the Cops3 Gene By Sirna Reduces Proliferation Omentioning

confidence: 99%

“…The number of lung cancer patients are increasing annually. Therapeutic approaches, such as chemotherapy, radiotherapy, and surgery have been widely used to treat lung cancer; however, these treatments offered little survival rate due to severe toxicity and drug resistance (Broker et al, 2002;Singh et al, 2008). Therefore, understanding of the carcinogenic mechanisms and genes involved in lung cancer cell's fast growth is of much importance in developing more precise treatments compared to conventional treatment methods.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via induction of Cell Cycle Arrest and Apoptosis

Wang

Cui²,

Li³

et al. 2012

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

The COPS3 gene has stimulating effect on cell proliferation and progression of osteosarcomas and related cells. However, the features of COPS3 and its potential application as a therapeutic target in other cancers has not yet been studied. In this study, therefore, the effect of COPS3 silencing via COPS3 siRNA on lung cancer cell proliferation was examined. Expression levels of COPS3 gene in COPS3 siRNA infected cells and control siRNA infected cells were compared with real time PCR and Western blot analysis. Cell proliferation levels were comprehensively analyzed by MTT, BrdU incorporationy, and colony formation assays. For mechanistic assessment the effects of COPS3 silencing on cell cycle and apoptosis were analyzed using flow cytometry. Results showed that successful silencing of the COPS3 gene at both translational and transcriptional levels significantly reduced the proliferation and colony formation by lung cancer cells (p<0.01). Flow cytometry showed cell cycle arrest in the G0/G1 phase after COPS3 silencing, and more importantly, apoptosis was induced as a result of COPS3 knockdown, which negatively affected cell survival. Therefore, these results provide another piece of important evidence that the COPS3 gene expressed in lung cancer cells may play a critical role in stimulating proliferation. Down-regulation of COPS3 could significantly inhibit lung cancer cell growth, which was most likely mediated via induction of cell cycle arrest in G0/G1 phase and apoptosis.

show abstract

Section: Silencing Of the Cops3 Gene By Sirna Reduces Proliferation Omentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via induction of Cell Cycle Arrest and Apoptosis

Wang

Cui²,

Li³

et al. 2012

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

show abstract

“…Many investigations have shown that the Nrf2-Keap1 pathway protects cells from many diseases including neurodegenerative disease and cancers [10,11]. Recently, several studies indicated that activation of Nrf2 is associated with tumorigenesis and resistance of chemotherapeutics in lung cancer, colon cancer, prostate cancer, and type II endometrial cancer [12][13][14][15]. Elevated expression of Nrf2 and its downstream genes contributed to MCF-7-derived tamoxifen resistance cell line, and using Nrf2 siRNA to block the expression of Nrf2 can reverse resistance of the cell lines to tamoxifen [16].…”

Section: Introductionmentioning

confidence: 99%

Combination of siRNA-directed gene silencing with epigallocatechin-3-gallate (EGCG) reverses drug resistance in human breast cancer cells

Esmaeili

2015

J Chem Biol

View full text Add to dashboard Cite

Elevated expression of NF-E2-related factor 2 (Nrf2), a nuclear transcription factor, is a frequent genetic abnormality seen in this malignancy and is an important contributor to chemoresistance in cancer therapy. In the present study, we investigated if Nrf2 was associated with drug resistance in tamoxifen-resistant MCF-7 (MCF-7/TAM) cells, and whether EGCG, major flavonoid isolated from green tea, could reverse drug resistance in MCF-7/TAM cells. Our results showed that the endogenous expression of Nrf2 as well as its target proteins heme oxygenase-1, NADP (H):quinone oxidoreductase in MCF-7/TAM cells was higher than that in MCF-7 cells. Epicatechin gallate (EGCG) significantly sensitizes MCF-7/TAM cells to tamoxifen and dramatically reduced Nrf2 expression at both the messenger RNA and protein, leading to a reduction of Nrf2-downstream genes. In addition, using siRNA technique, we found that the intracellular Nrf2 protein level was significantly decreased in MCF-7/ TAM cells and tamoxifen resistance was partially reversed by Nrf2 siRNA. Combination of siRNA-directed gene silencing with EGCG downregulated the Nrf2-dependent response and partly reversed tamoxifen resistance in MCF-7/TAM cells in a synergic manner. These results suggested that combining the chemotherapeutic effect of EGCG with siRNA-mediated Nrf2 knock-down results in the feasibility of using Nrf2 inhibitors to increase efficacy of chemotherapeutic drugs.

show abstract

“…Conversely, overexpression of Nrf2 in cancer cells that have low basal levels of Nrf2, enhanced resistance in a variety of cancer cells including neuroblastoma, breast, ovarian, prostate, lung, and pancreatic cancer cells (28)(29)(30)(31)(32). Combined use of Nrf2-siRNA and carboplatin inhibited the growth of A549 xenografts in mice (33). In addition, we have demonstrated that suppression of Nrf2 by Keap1 overexpression sensitized SPEC-2 cells, which are derived from type II endometrial cancer, and SPEC-2 xenografts to cisplatin (27).…”

mentioning

confidence: 99%

Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism

Ren

Villeneuve

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

565

506

View full text Add to dashboard Cite

The major obstacle in cancer treatment is the resistance of cancer cells to therapies. Nrf2 is a transcription factor that regulates a cellular defense response and is ubiquitously expressed at low basal levels in normal tissues due to Keap1-dependent ubiquitination and proteasomal degradation. Recently, Nrf2 has emerged as an important contributor to chemoresistance. High constitutive expression of Nrf2 was found in many types of cancers, creating an environment conducive for cancer cell survival. Here, we report the identification of brusatol as a unique inhibitor of the Nrf2 pathway that sensitizes a broad spectrum of cancer cells and A549 xenografts to cisplatin and other chemotherapeutic drugs. Mechanistically, brusatol selectively reduces the protein level of Nrf2 through enhanced ubiquitination and degradation of Nrf2. Consequently, expression of Nrf2-downstream genes is reduced and the Nrf2-dependent protective response is suppressed. In A549 xenografts, brusatol and cisplatin cotreatment induced apoptosis, reduced cell proliferation, and inhibited tumor growth more substantially when compared with cisplatin treatment alone. Additionally, A549-K xenografts, in which Nrf2 is expressed at very low levels due to ectopic expression of Keap1, do not respond to brusatol treatment, demonstrating that brusatol-mediated sensitization to cisplatin is Nrf2 dependent. Moreover, a decrease in drug detoxification and impairment in drug removal may be the primary mechanisms by which brusatol enhances the efficacy of chemotherapeutic drugs. Taken together, these results clearly demonstrate the effectiveness of using brusatol to combat chemoresistance and suggest that brusatol can be developed into an adjuvant chemotherapeutic drug.

show abstract

RNAi-Mediated Silencing of Nuclear Factor Erythroid-2–Related Factor 2 Gene Expression in Non–Small Cell Lung Cancer Inhibits Tumor Growth and Increases Efficacy of Chemotherapy

Cited by 348 publications

References 47 publications

Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via induction of Cell Cycle Arrest and Apoptosis

Silencing of the COPS3 Gene by siRNA Reduces Proliferation of Lung Cancer Cells Most Likely via induction of Cell Cycle Arrest and Apoptosis

Combination of siRNA-directed gene silencing with epigallocatechin-3-gallate (EGCG) reverses drug resistance in human breast cancer cells

Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism

Contact Info

Product

Resources

About