Nuclear Factor (Erythroid-Derived 2)-Like 2 Regulates Drug Resistance in Pancreatic Cancer Cells

Abstract

Objective To investigate the molecular basis of drug resistance in pancreatic cancer. Methods The expression of 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 ABCG2 regulation by over-expression or knockdown 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 over-expression 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 Since 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.

Hypoxia regulates ABCG2activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

“…It has been established that high levels of ABCG 2 are correlated with poor chemotherapy results for solid tumors. 18,19 Here, we demonstrated that higher levels of ABCG 2 are associated with hypoxia-induced chemoresistance in pancreatic cancer. Because gemcitabine is used as a first-line drug in the treatment of pancreatic cancer, we investigated the mechanism of p-ERK1/2-/HIF-1a-mediated regulation of ABCG 2 activity and the effects of ABCG 2 on gemcitabine response under hypoxic conditions in pancreatic cancer cells.…”

“…19 Therefore, ABCG 2 regulates drug response in pancreatic cancer, and further studies are needed to accurately characterize the mechanisms modulating ABCG 2 expression and function. Krishnamurthy et al were the first to demonstrate that hypoxia regulates ABCG 2 expression.…”

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

“…In the present study, nuclear NRF2 immunoreactivity was detected in 44% of the carcinoma cases, while it was positive in 2% of non-neoplastic breast tissues adjacent to the carcinoma and 4% of BBD tissues. Previous studies have demonstrated that NRF2 immunoreactivity is frequently detected in various human malignancies, such as breast (Loignon et al 2009, Karihtala et al 2011, Hartikainen et al 2012, lung (Inoue et al 2012), gastric (Wang et al 2011), pancreatic (Hong et al 2010), intrahepatic cholangiocellular (Wakai et al 2011), gallbladder (Wang et al 2010), endometrial (Chen et al 2010), and ovarian (Konstantinopoulos et al 2011) carcinomas, and its rate of immunopositivity ranged between 26 and 76% in these studies. The results of the immunohistochemical studies carried out in the present study also indicated a significant association between NRF2 status and immunoreactivity of NQO1, which is known to be an NRF2-induced cytoprotective gene (Lewis et al 2012), and subsequent in vitro studies revealed that both MCF7 and SK-BR-3 cells transfected with NRF2 siRNA had decreased NQO1 expression at both mRNA and protein levels.…”

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

“…For instance, suppression of endogenous Nrf2, either by transfecting Nrf2-siRNA or overexpressing Keap1, sensitized cancer cells to chemotherapeutic drugs. 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).…”