Different roles for K+ channels in cisplatin-resistant cell lines argue against a critical role for these channels in cisplatin resistance.
Cisplatin resistance has been associated with altered K+ fluxes. Here, we focused our investigations on the detection of K+ channels in a series of cisplatin-resistant (CP-r) cells with increasing resistance and on the functional relationship of these K+ channels to resistance. Microarray analysis and confocal microscopy indicated that there was overexpression of the ether-a-gogo gene (HERG) and the inwardly rectifying potassium channel gene (TWIK) in a human epidermal KB and human liver BEL-7404 carcinoma cell line series selected for cisplatin resistance. With increased resistance, the plasma membrane potential, but not the mitochondrial membrane potential, also increases in these two series. For these reasons, we conducted cell proliferation studies in the presence of either antibodies directed against the detected K+ channels, omeprazole (a H+ pump inhibitor) or a specific inhibitor of the HERG channel (WAY-123398-A-5). The antibodies and omeprazole influenced cell growth only very slightly. The specific K+ channel blocker did not alter cisplatin resistance. We also observed that manipulation of K+ fluxes with antibodies and the H+ pump with omeprazole resulted in opposite effects on cisplatin resistance in these two cell lines. We conclude that K+ and H+ homeostasis are not critical factors in cisplatin resistance since they affect cisplatin resistance differently in KB and BEL-7404 cells.
Liang
Xing-Jie
XJ
Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda 20892-4256, Maryland, USA.
Taylor
Barbara
B
Cardarelli
Carol
C
Yin
Jun-Jie
JJ
Annereau
Jean-Philippe
JP
Garfield
Susan
S
Wincovitch
Stephen
S
Szakács
Gergely
G
Gottesman
Michael M
MM
Aszalos
Adorjan
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D007624:KB Cells; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D009853:Omeprazole / Q000494:pharmacology; D010101:Oxygen Consumption; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology
D000970:Antineoplastic Agents; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D009853:Omeprazole; D002945:Cisplatin; D011188:Potassium