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( Sarala Manandhar ),( Bo Hyun Choi ),( Kyeong Ah Jung ),( In Geun Ryoo ),( Min Gu Song ),( Su Jin Kang ),( Han Gon Choi ),( Jung Ae Kim ),( Pil Hoon Park ),( Mi Kyoung Kwa ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
NF-E2-related factor 2 (NRF2) is a transcription factor that regulates the expression of various antioxidant and detoxifying enzymes. Although the benefit of NRF2 in cancer prevention is well established, its role in cancer pathobiology was recently discovered. In this study, the role of NRF2 in tumor growth and docetaxel sensitivity was investigated in ErbB2-overexpressing ovarian carcinomaSKOV3 cells. Interfering RNA-mediated stable inhibition of NRF2 in SKOV3 cells repressed NRF2signaling, resulting in cell growth arrest at G(0)/G(1) phase and tumor growth retardation in mouse xenografts. Microarray analysis revealed that ErbB2 expression is substantially reduced in NRF2-inhibited SKOV3 and this was further confirmed by RT-PCR and immunoblot analysis. Repression ofErbB2 led to a decrease in phospho-AKT and enhanced p27 protein, reinforcing the effect of NRF2knockdown on SKOV3 growth. Furthermore, NRF2 inhibition-mediated ErbB2 repression increases the sensitivity of these cells to docetaxel cytotoxicity and apoptosis. The linkage between NRF2 andErbB2 was confirmed in the ErbB2-positive breast cancer cell line BT-474: NRF2 knockdown suppressed ErbB2 expression and enhanced docetaxel sensitivity. Our results provide insight into the coordinated regulation of signaling molecules responding to environmental stress and suggest thatNRF2 modulation might be a therapeutic strategy to limit tumor growth and enhance sensitivity to taxane-based chemotherapy. ⓒ 2012 Elsevier Lnc. All rights reserved.
Emerging role of RUNX3 in the regulation of tumor microenvironment
( Sarala Manandhar ),( You Mie Lee ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.4
A number of genes have been therapeutically targeted to relieve cancer, but cancer relapse is still a growing issue. The concept that the surrounding tumor environment is critical for the progression of cancer may foster an answer to the issue of cancer malignancy. Runt domain transcription factors (RUNX1, 2, and 3) are evolutionarily conserved and have been intensively studied for their roles in normal development and pathological conditions. During tumor growth, a hypoxic microenvironment and infiltration of the tumor by immune cells are common phenomena. In this review, we briefly introduce the consequences of hypoxia and immune cell infiltration into the tumor microenvironment with a focus on RUNX3 as a critical regulator. Furthermore, based on our current knowledge of the functional role of RUNX3 in hypoxia and immune cell maintenance, a probable therapeutic intervention is suggested for the effective management of tumor growth and malignancy. [BMB Reports 2018; 51(4): 174-181]
Effect of Stable Inhibition of NRF2 on Doxorubicin Sensitivity in Human Ovarian Carcinoma OV90 Cells
Manandhar, Sarala,Lee, Sang-Whan,Kwak, Mi-Kyoung 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.5
The transcription factor NRF2 defends the cell from oxidative stress by up-regulating a large number of antioxidant genes through its binding with antioxidant response element on gene promoters. Cancer cells are known to possess high levels of antioxidant genes that increases survival in cancer microenvironment of oxidative stress, particularly in the treatment with anticancer agents. In the current study we have examined the role of the NRF2 in doxorubicin sensitivity and tumor growth by establishing stable cell line expressing NRF2 shRNA in the human ovarian carcinoma cell line OV90. On knockdown of NRF2 through NRF2-specific shNRF2 expressing lentiviral plasmid, antioxidant response element-driven luciferase activity as well as the expression of NRF2-target genes were significantly suppressed compared to nonspecific scrambled RNA (scRNA) expressing cells. In addition, shNRF2 expressing OV90-shNRF2 cells showed a reduction in total GSH levels by 82% and cell growth was observed to be significantly retarded compared to scRNA control cells. Furthermore, stable inhibition of NRF2 sensitized OV90 cells were seen following doxorubicin treatment as shown by the analysis with MTT assay and propidium iodide-fluorescence-activated cell sorting. OV90-shNRF2 cells showed higher levels of cell death and apoptosis in response to doxorubicin than OV90-scRNA cells. While, when BALBc (nu/nu) mice with OV90 tumor xenograft in the flanks were injected with NRF2 shRNA containing viral particles and treated with doxorubicin a pattern of retardation in tumor growth was seen in shRNA group compared to scRNA group, but this difference was not statistically significant. In conclusion, we propose that the NRF2 signaling might be a molecular target to repress tumor growth and enhance cytotoxic effects of anticancer agent in cancer cells.