Abstract
Multidrug resistance (MDR) due to enhanced drug efflux activity of tumor cells can severely impact the efficacy of antitumor therapies. We recently showed that increased activity of the efflux transporter P-glycoprotein (P-gp) associated with activation of Snail transcriptional regulators may be mediated mainly by moesin in lung cancer cells. Here, we aimed to systematically evaluate the relationships among mRNA expression levels of efflux transporters (P-gp, breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2)), scaffold proteins (ezrin (Ezr), radixin (Rdx), and moesin (Msn); ERM proteins), and SNAI family members (Snail, Slug, and Smac) in clinical lung cancer and noncancer samples. We found high correlations between relative (cancer/noncancer) mRNA expression levels of Snail and Msn, Msn and P-gp, Slug and MRP2, and Smuc and BCRP. These findings support our previous conclusion that Snail regulates P-gp activity via Msn and further suggest that Slug and Smuc may contribute to the functional regulation of MRP2 and BCRP, respectively, in lung cancer cells. This trial is registered with UMIN000023923.
Highlights
Lung cancer is the leading cause of cancer death in the United States
Slug mRNA levels showed a high correlation with MRP2 (r 0.800), and Smuc mRNA levels showed a high correlation with BCRP (r 0.818) (Figure 1)
We reported that Snail-overexpressing HCC827 cells showed significantly increased mRNA expression of Msn compared with Mock cells, whereas the expression levels of Ezr and Rdx were unchanged [12]. e protein expression level of Msn was consistent with the mRNA expression level
Summary
Lung cancer is the leading cause of cancer death in the United States. almost one-quarter of all cancer deaths are due to lung cancer [1], and among patients with non-small-cell lung cancer (NSCLC), only 26% are alive for more than 5 years after diagnosis [2]. Surgical operation is not feasible, and chemotherapy and adjuvant therapy are used as first-line treatments [3] These treatments are often adversely affected by the emergence of multidrug resistance (MDR), i.e., resistance to multiple mechanistically and structurally unrelated antitumor drugs [4], resulting in a poor prognosis [5]. Canadian Journal of Infectious Diseases and Medical Microbiology resistance protein (BCRP, ATP-binding cassette subfamily G member 2 (ABCG2)), and multidrug resistance-associated protein 2 (MRP2, ATP-binding cassette subfamily C member 2 (ABCC2)), leading to reduced accumulation of anticancer drugs in cells [6]. BCRP has been suggested to be closely associated with resistance of NSCLC to topoisomerase I inhibitors, including irinotecan and its active metabolite, SN-38 [9], while MRP2 contributes to cisplatin resistance [10]. In HCC827 human lung adenocarcinoma cells, Ezr or Msn knockdown significantly reduced Rhodamine123 (Rho123) efflux, which suggests that Ezr and/or Msn are involved in the regulation of P-gp activity in the lung [14]
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