Nrf2 영구 넉다운 난소암 세포주의 Proteasome 저해 항암제 Bortezomib에 대한 감수성 증가 = Enhanced Sensitivity to Proteasome Inhibitor Bortezomib in Nrf2 Knockdown Ovarian Cancer Cells

다국어 초록 (Multilingual Abstract)

NF-E2-related factor 2 (Nrf2), a master regulator of antioxidant genes in animals, has been associated with the resistance of cancer cells to several cytotoxic chemotherapeutics. Bortezomib, a reversible inhibitor of the 26S proteasome, is a novel class anti-cancer therapeutics approved for the treatment of refractory multiple myeloma. However, the molecular mechanism of drug-resistance remains elusive. In the present study, bortezomib sensitivity has been investigated in Nrf2 knockdown ovarian cancer cells. When Nrf2 expression is stably repressed using interfering RNA expression, bortezomibinduced apoptosis and cell death were significantly enhanced compared to nonspecific RNA control cells. Knockdown cells showed elevated expression in the catalytic subunit PSMB5, PSMB6, and PSMB7 compared to the control, and failed to induce heme oxygenase-1 expression following bortezomib treatment. These indicate that differential proteasome levels and altered expression of stress-response genes could be underlying mechanisms of bortezomib sensitization in Nrf2-inhibited ovarian cancer cells.

참고문헌 (Reference)

1 Glickman, M. H, "The ubiquitinproteasome proteolytic pathway: destruction for the sake of construction" 82 : 373-, 2002

2 Maines, M. D, "The heme oxygenase system: update 2005" 7 : 1761-, 2005

3 Voges, D., "The 26S proteasome: a molecular machine designed for controlled proteolysis" 68 : 1015-, 1999

4 Kwak, M. K, "Targeting NRF2 signaling for cancer chemoprevention" ACADEMIC PRESS INC ELSEVIER SCIENCE 244 : 66-, 2010

5 Padmanabhan, B., "Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer" 21 : 689-, 2006

6 Busse, A, "Sensitivity of tumor cells to proteasome inhibitors is associated with expression levels and composition of proteasome subunits" 112 : 659-, 2008

7 Cho, J. M, "Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: Implication to cancer cell resistance" ELSEVIER IRELAND LTD 260 : 96-108, 2008

8 Singh, A., "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" 68 : 7975-, 2008

9 Wu, W. T., "Proteasome inhibitors up-regulate haem oxygenase-1 gene expression: requirement of p38 MAPK (mitogen-activated protein kinase) activation but not of NF-kappaB (nuclear factor kappaB) inhibition" 379 : 587-, 2004

10 Manandhar, S, "NRF2 inhibition represses ErbB2 signaling in ovarian carcinoma cells: Implications for tumor growth retardation and docetaxel sensitivity. (Submitted)"

11 Hayes, J. D, "NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer" 34 : 176-, 2009

12 Li, W, "Molecular mechanisms of Nrf2- mediated antioxidant response" 48 : 91-, 2009

13 Kobayashi, M, "Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation" 7 : 385-, 2005

14 Oerlemans, R, "Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein" 112 : 2489-, 2008

15 Sekhar, K. R., "Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for gamma-glutamylcysteine synthetase" 270 : 311-, 2000

16 Chen, J, "Increasing expression of heme oxygenase-1 by proteasome inhibition protects astrocytes from heme-mediated oxidative injury" 2 : 189-, 2005

17 Nguyen, T., "Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome" 278 : 4536-, 2003

18 Fuchs, D, "Increased expression and altered subunit composition of proteasomes induced by continuous proteasome inhibition establish apoptosis resistance and hyperproliferation of Burkitt lymphoma cells" 103 : 270-, 2008

19 Shibata, T, "Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer" 135 : 1358-, 2008

20 Yamamoto, N., "Elevation of heme oxygenase-1 by proteasome inhibition affords dopaminergic neuroprotection" 88 : 1934-, 2010

21 Singh, A, "Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer" 3 : 420-, 2006

22 Nalepa, G., "Drug discovery in the ubiquitin-proteasome system" 5 : 596-, 2006

23 Shibata, T, "Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy" 105 : 13568-, 2008

24 Hayes, J. D, "Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway" 13 : 1713-, 2010

25 Richardson, P. G, "Bortezomib: proteasome inhibition as an effective anticancer therapy" 1 : 161-, 2005

26 Roccaro, A. M, "Bortezomib as an antitumor agent" 7 : 441-, 2006

27 Itoh, K, "An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements" 236 : 313-, 1997

28 Kraus, M., "Activity patterns of proteasome subunits reflect bortezomib sensitivity of hematologic malignancies and are variable in primary human leukemia cells" 21 : 84-, 2007

29 Shim, G. S., "Acquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway" ELSEVIER SCIENCE INC 47(11) : 1619-, 2009

30 Richardson, P. G, "A phase 2 study of bortezomib in relapsed, refractory myeloma. N" 348 : 2609-, 2003