Loss of Kv and MaxiK currents associated with increased MRP1 expression in small cell lung carcinoma

Abstract

Regulatory volume decrease and exocrine secretion studies suggest a functional relationship between K+ and organic anion efflux. To test the hypothesis that the expression of K+ channels and MRP1 is reciprocally related, we employed the patch clamp and RT-PCR techniques on weakly (H69) and strongly MRP1-expressing (H69AR) small cell lung cancer cells. H69AR cells do not express the time- and voltage-dependent delayed rectifying K+ current (Kv) reported earlier in H69 cells and confirmed here. About 80% of the Kv current in H69 cells inactivated at 0 mV, allowing us to identify other K+ currents present in these cells. Whole-cell currents from cells dialyzed and bathed in K-gluconate as the major ions exhibited inward rectification in both cell types. Inwardly rectifying (Kir) currents in both H69 and H69AR cells showed time-dependent activation and slow inactivation at large negative potentials. H69 cells also express a threefold larger Ca2+ -stimulated K+ -selective and iberiotoxin-sensitive current relative to H69AR cells. In excised inside-out patches exposed to 145 mM symmetrical K+ solutions, H69 cells expressed a voltage- and Ca2+ -sensitive large conductance (128 +/- 5 pS) K+ channel (MaxiK). MaxiK-like currents were not observed at the whole-cell or single-channel level in H69AR cells. RT-PCR identified MaxiKalpha transcripts in H69 but not H69AR cells. These results indicate that two K+ currents (MaxiK and Kv) and the organic anion transporter MRP1 are reciprocally expressed in H69 and H69AR cells.

Upregulation of the inwardly rectifying potassium channel Kir2.1 (KCNJ2) modulates multidrug resistance of small-cell lung cancer under the regulation of miR-7 and the Ras/MAPK pathway

“…In addition to the potential therapeutic impact of KCNJ2/Kir2.1, our studies shed light on the mechanisms by which KCNJ2/Kir2.1 mediates MDR in SCLC. Several studies have confirmed that MRP1/ABCC1 is highly expressed in H69AR cells [ 30 , 31 ], and may be closely related to chemoresistance in SCLC [ 22 ]. Enyeart et al showed that K + channels, including KCNJ2/Kir2.1, might function with MRP1/ABCC1 [ 32 ].…”

Ion Channels: New Actors Playing in Chemotherapeutic Resistance

“…Additionally, the Leanza group demonstrated, in several cancer cell lines, a similar relationship between reduced expression of Kv1.1 and Kv1.3 and decreased sensitivity to drugs, provoking mitochondrial-induced apoptotic death [106]. Another study conducted using small cell lung carcinoma cells demonstrated a relation between K + channel expression profile and drug resistance [107]. More precisely, authors demonstrated that the expression level of BKCa and Kv channels was inversely correlated to the MRP1 expression levels.…”