Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide

Nikhil M. Patel, Shinichi Nozaki, Nicholas H. Shortle, Poornima Bhat-Nakshatri, Thomas R. Newton, Susan Rice, Vasily Gelfanov, H. Boswell, Robert J. Goulet, George W. Sledge, Harikrishna Nakshatri

Research output: Contribution to journalArticle

243 Citations (Scopus)

Abstract

The transcription factor nuclear factor-κB (NF-κB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-κB remains sequestered in an inactive state by cytoplasmic inhibitor-of-κB (IκB) proteins. NF-κB translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines. We and others have shown previously that NF-κB is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-κB 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-κB in certain breast cancer cells. We also demonstrate that NF-κB-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modified to overexpress IκBα 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-κB on paclitaxel-sensitivity appears to be specific to cancer cells because normal fibroblasts derived from embryos lacking p65 subunit of NF-κB 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 IκBα by inhibiting NF-κB 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-κB to chemotherapeutic drugs.

Original languageEnglish
Pages (from-to)4159-4169
Number of pages11
JournalOncogene
Volume19
Issue number36
StatePublished - Aug 24 2000

Fingerprint

Paclitaxel
Breast Neoplasms
Tanacetum parthenium
Apoptosis
Superoxide Dismutase
Embryonic Structures
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
G2 Phase Cell Cycle Checkpoints
Neoplasms
parthenolide
G2 Phase
Neoplasm Genes
Cell Division
Genes
Intercellular Signaling Peptides and Proteins
Cell Cycle
Cell Death
Anti-Inflammatory Agents
Transcription Factors
Fibroblasts

Keywords

  • Breast cancer
  • NF-κB
  • Paclitaxel
  • Parthenolide

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Patel, N. M., Nozaki, S., Shortle, N. H., Bhat-Nakshatri, P., Newton, T. R., Rice, S., ... Nakshatri, H. (2000). Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide. Oncogene, 19(36), 4159-4169.

Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide. / Patel, Nikhil M.; Nozaki, Shinichi; Shortle, Nicholas H.; Bhat-Nakshatri, Poornima; Newton, Thomas R.; Rice, Susan; Gelfanov, Vasily; Boswell, H.; Goulet, Robert J.; Sledge, George W.; Nakshatri, Harikrishna.

In: Oncogene, Vol. 19, No. 36, 24.08.2000, p. 4159-4169.

Research output: Contribution to journalArticle

Patel, NM, Nozaki, S, Shortle, NH, Bhat-Nakshatri, P, Newton, TR, Rice, S, Gelfanov, V, Boswell, H, Goulet, RJ, Sledge, GW & Nakshatri, H 2000, 'Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide', Oncogene, vol. 19, no. 36, pp. 4159-4169.
Patel NM, Nozaki S, Shortle NH, Bhat-Nakshatri P, Newton TR, Rice S et al. Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide. Oncogene. 2000 Aug 24;19(36):4159-4169.
Patel, Nikhil M. ; Nozaki, Shinichi ; Shortle, Nicholas H. ; Bhat-Nakshatri, Poornima ; Newton, Thomas R. ; Rice, Susan ; Gelfanov, Vasily ; Boswell, H. ; Goulet, Robert J. ; Sledge, George W. ; Nakshatri, Harikrishna. / Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide. In: Oncogene. 2000 ; Vol. 19, No. 36. pp. 4159-4169.
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