Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization independent activation of the nuclear factor-kappaB/IkappaB kinase signal pathway.
Molecular mechanisms underlying epothilone-induced apoptotic cell death were investigated in SW620 human colon cancer cells. Treatment with epothilone B and D at different concentrations (1-100 nmol/L) dose-dependently inhibited cell growth and caused cell cycle arrest at G2-M, which was followed by apoptosis. Consistent with this induction of apoptotic cell death, epothilone B and D enhanced the constitutional activation of nuclear factor-kappaB (NF-kappaB) via IkappaB degradation through IkappaB kinase (IKKalpha and IKKbeta) activation, and this resulted in p50 and p65 translocation to the nucleus. Moreover, cells treated with sodium salicylic acid, an IKK inhibitor, or transiently transfected with mutant IKKalpha and beta did not show epothilone-induced cell growth inhibition or p50 translocation, although p65 was still translocated to the nucleus. Treatment with epothilone B and D also enhanced beta-tubulin polymerization and the formation of p50/beta-tubulin complex. However, beta-tubulin polymerization was not inhibited in the cells treated by sodium salicylic acid or transiently transfected with mutant IKKalpha and beta. Moreover, epothilone B and D increased the expressions of NF-kappaB-dependent apoptotic cell death regulatory genes, i.e., Bax, p53, and the active form of caspase-3, but reduced Bcl-2 expression, and these actions were partially reversed by salicylic acid. In addition, caspase-3 inhibitor reduced epothilone B-induced cell death and NF-kappaB activation. These findings suggest that the activation of NF-kappaB/IKK signals plays an important role in the epothilone-induced apoptotic cell death of SW620 colon cancer cells in a tubulin polymerization-independent manner.
Lee
Seung Ho
SH
College of Pharmacy, Chungbuk National University, 410 SungBong-Ro, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea.
Son
Seung Mo
SM
Son
Dong Ju
DJ
Kim
Sun Mi
SM
Kim
Tack Joong
TJ
Song
Sukgil
S
Moon
Dong Cheul
DC
Lee
Hyo Won
HW
Ryu
Jae Chun
JC
Yoon
Do-Young
DY
Hong
Jin Tae
JT
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D034261:Epothilones / Q000494:pharmacology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008156:Luciferases / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020156:Salicylic Acid / Q000494:pharmacology; D015398:Signal Transduction; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D034261:Epothilones; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D008156:Luciferases; D051550:I-kappa B Kinase; D053148:Caspase 3; D020156:Salicylic Acid; C114026:desoxyepothilone B; C093788:epothilone B