Involvement of Ca2+ influx in the mechanism of tamoxifen-induced apoptosis in HepG2 human hepatoblastoma cells.
The signaling mechanism of tamoxifen (TAM)-induced apoptosis was investigated in HepG2 human hepatoblastoma cells which do not express the estrogen receptor (ER). TAM induced cytotoxicity and DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. TAM increased the intracellular concentration of Ca2+. This effect was completely inhibited by the extracellular Ca2+ chelation with EGTA. TAM also induced a Mn2+ influx, indicating that TAM activated Ca2+ influx pathways. This action of TAM was significantly inhibited by flufenamic acid (FA), a known non-selective cation channel blocker. Quantitative analysis of apoptosis by flow cytometry revealed that treatment with either FA or BAPTA, an intracellular Ca2+ chelator, significantly inhibited TAM-induced apoptosis. These results suggest that intracellular Ca2+ signals may play a central role in the mechanism of the TAM-induced apoptotic cell death in ER-negative HepG2 cells.
Kim
J A
JA
Physiology Section, College of Pharmacy, Yeungnam University, Kyongsan, South Korea.
Kang
Y S
YS
Jung
M W
MW
Lee
S H
SH
Lee
Y S
YS
D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005439:Flufenamic Acid / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D018197:Hepatoblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008345:Manganese / Q000493:pharmacokinetics; D008564:Membrane Potentials / Q000187:drug effects; D011960:Receptors, Estrogen; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D002121:Calcium Channel Blockers; D002614:Chelating Agents; D005456:Fluorescent Dyes; D007473:Ion Channels; D011960:Receptors, Estrogen; D013629:Tamoxifen; D008345:Manganese; D004533:Egtazic Acid; D005439:Flufenamic Acid; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; D016257:Fura-2