Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide.
The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-kappaB remains sequestered in an inactive state by cytoplasmic inhibitor-of-kappaB (IkappaB) proteins. NF-kappaB translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines. We and others have shown previously that NF-kappaB is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-kappaB leads to overexpression of the anti-apoptotic genes c-inhibitor of apoptosis 2 (c-IAP2) and manganese superoxide dismutase (Mn-SOD) in breast cancer cells. Furthermore, expression of the anti-apoptotic tumor necrosis factor receptor associated factor 1 (TRAF1) and defender-against cell death (DAD-1) is regulated by NF-kappaB in certain breast cancer cells. We also demonstrate that NF-kappaB-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modified to overexpress IkappaBalpha required lower concentrations of paclitaxel to arrest at the G2/M phase of the cell cycle and undergo apoptosis when compared to parental cells. The effect of NF-kappaB on paclitaxel-sensitivity appears to be specific to cancer cells because normal fibroblasts derived from embryos lacking p65 subunit of NF-kappaB and wild type littermate embryos were insensitive to paclitaxel-induced G2/M cell cycle arrest. Parthenolide, an active ingredient of herbal remedies such as feverfew (tanacetum parthenium), mimicked the effects of IkappaBalpha by inhibiting NF-kappaB DNA binding activity and Mn-SOD expression, and increasing paclitaxel-induced apoptosis of breast cancer cells. These results suggest that active ingredients of herbs with anti-inflammatory properties may be useful in increasing the sensitivity of cancers with constitutively active NF-kappaB to chemotherapeutic drugs. Oncogene (2000) 19, 4159 - 4169
Patel
N M
NM
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, IN 46202, USA.
Nozaki
S
S
Shortle
N H
NH
Bhat-Nakshatri
P
P
Newton
T R
TR
Rice
S
S
Gelfanov
V
V
Boswell
S H
SH
Goulet
R J
RJ
Sledge
G W
GW
Nakshatri
H
H
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D010946:Plants, Medicinal; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C096021:Dad-1 protein, C elegans; D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011506:Proteins; D012097:Repressor Proteins; D012717:Sesquiterpenes; D047990:TNF Receptor-Associated Factor 1; D000072000:NF-KappaB Inhibitor alpha; C002669:parthenolide; D004247:DNA; D013482:Superoxide Dismutase; D017239:Paclitaxel