Abstract
BackgroundKCNJ2/Kir2.1, a member of the classical inwardly rectifying potassium channel family, is commonly expressed in a wide range of tissues and cell types. Previous studies indicated that Kir2.1 may be associated with SCLC multidrug resistance (MDR). However, whether Kir2.1 can regulate MDR and its underlying mechanisms remain poorly understood in SCLC.MethodsKCNJ2/Kir2.1 expression was examined in tissues from fifty-two SCLC cases by immunohistochemistry. Overexpression or knockdown of KCNJ2/Kir21 was performed in multidrug-resistant SCLC cell lines (H69AR and H446AR) and their parental cell lines (H69 and H446) to assess its influence on cell growth, apoptosis, the cell cycle and chemoresistance.ResultsKCNJ2/Kir2.1 was expressed in 44.23% (23/52) of SCLC tissues. Overexpression of KCNJ2/Kir2.1 was correlated with the clinical stage and chemotherapy response in SCLC patients. Knockdown of KCNJ2/Kir2.1 expression using KCNJ2/Kir2.1 shRNA in H69AR and H446AR cells inhibited cell growth and sensitized the cancer cells to chemotherapeutic drugs by increasing cell apoptosis and cell cycle arrest. Forced KCNJ2/Kir2.1 expression in H69 and H446 cells promoted cell growth and enhanced multidrug resistance via reduced drug-induced apoptosis accompanied by cell cycle arrest. KCNJ2/Kir2.1 expression was also influenced by PKC and MEK inhibitors. In addition, multidrug resistance protein 1 (MRP1/ABCC1) was confirmed to interact with KCNJ2/Kir2.1 by Co-IP assays.ConclusionsKCNJ2/Kir2.1 modulates cell growth and drug resistance by regulating MRP1/ABCC1 expression and is simultaneously regulated by the Ras/MAPK pathway and miR-7. KCNJ2/Kir2.1 may be a prognostic predictor and a potentially novel target for interfering with chemoresistance in SCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0298-0) contains supplementary material, which is available to authorized users.
Highlights
KCNJ2/Kir2.1, a member of the classical inwardly rectifying potassium channel family, is commonly expressed in a wide range of tissues and cell types
80-90% of Small-cell lung cancer (SCLC) patients are initially responsive to chemotherapy, most of them succumb to the disease within a year due to rapidly developing multidrug resistance (MDR) [3,4]
Kir2.1 expression is associated with the clinical stage and the chemotherapy Response of SCLC patients To investigate the clinical features of Kir2.1 expression in SCLC, we first examined the expression levels of Kir2.1 in 52 SCLC specimens and 15 normal lung tissues by immunohistochemistry (IHC)
Summary
KCNJ2/Kir2.1, a member of the classical inwardly rectifying potassium channel family, is commonly expressed in a wide range of tissues and cell types. Previous studies indicated that Kir2.1 may be associated with SCLC multidrug resistance (MDR). Whether Kir2.1 can regulate MDR and its underlying mechanisms remain poorly understood in SCLC. Small-cell lung cancer (SCLC), the most aggressive type of lung cancer, constitutes approximately 15-18% of all lung cancers [2]. According to the Veterans Administration Lung Group system, SCLC is traditionally defined by a two-stage classification system that includes limited disease and extensive disease. Chemotherapy remains the first treatment option for SCLC patients. 80-90% of SCLC patients are initially responsive to chemotherapy, most of them succumb to the disease within a year due to rapidly developing multidrug resistance (MDR) [3,4]. MDR has become the main obstacle to the treatment of SCLC and a central issue in improving its prognosis
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