OBJECTIVE: To investigate the molecular basis of drug resistance in pancreatic cancer. METHODS: The expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) levels in pancreatic cancer tissues and cell lines was analyzed. Clinical relevance between Nrf2 activation and drug resistance was demonstrated by measuring cell viability after Nrf2 and adenosine 5'-triphosphate-binding cassette, subfamily G member 2 (ABCG2) regulation by overexpression or knock-down of these genes. Activity of ABCG2 was measured by Hoechst 33342 staining. RESULTS: Abnormally elevated Nrf2 protein levels were observed in pancreatic cancer tissues and cell lines relative to normal pancreatic tissues. Increasing Nrf2 protein levels either by overexpression of exogenous Nrf2 or by activating endogenous Nrf2 resulted in increased drug resistance. Conversely, a reduction in endogenous Nrf2 protein levels or inactivation of endogenous Nrf2 resulted in decreased drug resistance. These changes in drug resistance or sensitivity were also positively correlated to the expression levels of Nrf2 downstream genes. Similarly, the expression of ABCG2 was correlated with drug resistance. CONCLUSIONS: Because the intrinsic drug resistance of pancreatic cancers is, in part, due to abnormally elevated Nrf2 protein levels, further research on regulating Nrf2 activity may result in the development of novel pancreatic cancer therapies.
OBJECTIVE: To investigate the molecular basis of drug resistance in pancreatic cancer. METHODS: The expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) levels in pancreatic cancer tissues and cell lines was analyzed. Clinical relevance between Nrf2 activation and drug resistance was demonstrated by measuring cell viability after Nrf2 and adenosine 5'-triphosphate-binding cassette, subfamily G member 2 (ABCG2) regulation by overexpression or knock-down of these genes. Activity of ABCG2 was measured by Hoechst 33342 staining. RESULTS: Abnormally elevated Nrf2 protein levels were observed in pancreatic cancer tissues and cell lines relative to normal pancreatic tissues. Increasing Nrf2 protein levels either by overexpression of exogenous Nrf2 or by activating endogenous Nrf2 resulted in increased drug resistance. Conversely, a reduction in endogenous Nrf2 protein levels or inactivation of endogenous Nrf2 resulted in decreased drug resistance. These changes in drug resistance or sensitivity were also positively correlated to the expression levels of Nrf2 downstream genes. Similarly, the expression of ABCG2 was correlated with drug resistance. CONCLUSIONS: Because the intrinsic drug resistance of pancreatic cancers is, in part, due to abnormally elevated Nrf2 protein levels, further research on regulating Nrf2 activity may result in the development of novel pancreatic cancer therapies.
Authors: Min Kim; Heth Turnquist; John Jackson; Magda Sgagias; Ying Yan; Maokai Gong; Michael Dean; John G Sharp; Kenneth Cowan Journal: Clin Cancer Res Date: 2002-01 Impact factor: 12.531
Authors: J Alam; C Wicks; D Stewart; P Gong; C Touchard; S Otterbein; A M Choi; M E Burow; J Tou Journal: J Biol Chem Date: 2000-09-08 Impact factor: 5.157
Authors: Dongmei Ren; Nicole F Villeneuve; Tao Jiang; Tongde Wu; Alexandria Lau; Henry A Toppin; Donna D Zhang Journal: Proc Natl Acad Sci U S A Date: 2011-01-04 Impact factor: 11.205
Authors: Melissa L Fishel; Xue Wu; Cecilia M Devlin; Derek P Logsdon; Yanlin Jiang; Meihua Luo; Ying He; Zhangsheng Yu; Yan Tong; Kelsey P Lipking; Anirban Maitra; N V Rajeshkumar; Glenda Scandura; Mark R Kelley; Mircea Ivan Journal: J Biol Chem Date: 2014-12-09 Impact factor: 5.157