Paclitaxel Sensitivity of Breast Cancer Cells With Constitutively Active NF-kappaB Is Enhanced by IkappaBalpha Super-Repressor and Parthenolide

Oncogene. 2000 Aug 24;19(36):4159-69. doi: 10.1038/sj.onc.1203768.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins
  • Blotting, Northern
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Caenorhabditis elegans Proteins*
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • I-kappa B Proteins*
  • Inhibitor of Apoptosis Proteins
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Paclitaxel / pharmacology*
  • Plants, Medicinal
  • Protein Binding
  • Proteins / metabolism
  • Repressor Proteins / metabolism
  • Sesquiterpenes / pharmacology*
  • Superoxide Dismutase / metabolism
  • TNF Receptor-Associated Factor 1
  • Tumor Cells, Cultured

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents, Phytogenic
  • Apoptosis Regulatory Proteins
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Dad-1 protein, C elegans
  • I-kappa B Proteins
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Proteins
  • Repressor Proteins
  • Sesquiterpenes
  • TNF Receptor-Associated Factor 1
  • NF-KappaB Inhibitor alpha
  • parthenolide
  • DNA
  • Superoxide Dismutase
  • Paclitaxel