Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase

Harikrishna Nakshatri, Susan E. Rice, Poornima Bhat-Nakshatri

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

The antitumor activity of the sesquiterpene lactone parthenolide, an active ingredient of medicinal plants, is believed to be due to the inhibition of DNA binding of transcription factors NF-κB and STAT-3, reduction in MAP kinase activity and the generation of reactive oxygen. In this report, we show that parthenolide activates c-Jun N-terminal kinase (JNK), which is independent of inhibition of NF-κB DNA binding and generation of reactive oxygen species. Parthenolide reversed resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Cancer cells treated with a combination of TRAIL and parthenolide underwent massive typical apoptosis and atypical apoptosis involving the loss of plasma membrane integrity. JNK activity is necessary for the parthenolide-induced sensitization to TRAIL because a dominant-negative JNK or the JNK inhibitor SP600125 reduced TRAIL plus parthenolide-induced apoptosis. Parthenolide induced phosphorylation of Bid and increased TRAIL-dependent cleavage of Bid without affecting caspase 8 activities. Cytochrome c but not Smac/DIABLO was released from the mitochondria in cells treated with parthenolide alone. Parthenolide through JNK increased the TRAIL-mediated degradation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP). Enhanced XIAP cleavage correlated with increased and prolonged caspase 3 activity and PARP cleavage, suggesting that the sensitization to TRAIL involves 'feed forward' activation of caspase 3. These results identify a new antitumor activity of parthenolide, which can be exploited to reverse resistance of cancer cells to TRAIL, particularly those with elevated XIAP levels.

Original languageEnglish
Pages (from-to)7330-7344
Number of pages15
JournalOncogene
Volume23
Issue number44
DOIs
StatePublished - Sep 23 2004

Fingerprint

JNK Mitogen-Activated Protein Kinases
Antineoplastic Agents
Tumor Necrosis Factor-alpha
Apoptosis
Breast Neoplasms
Ligands
Caspase 3
X-Linked Inhibitor of Apoptosis Protein
parthenolide
STAT Transcription Factors
Caspase 8
Sesquiterpenes
DNA
Lactones
Medicinal Plants
Cytochromes c
Reactive Oxygen Species
Neoplasms
Mitochondria
Phosphotransferases

Keywords

  • Apoptosis
  • Breast cancer
  • JNK
  • NF-κB
  • Parthenolide
  • TRAIL

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase. / Nakshatri, Harikrishna; Rice, Susan E.; Bhat-Nakshatri, Poornima.

In: Oncogene, Vol. 23, No. 44, 23.09.2004, p. 7330-7344.

Research output: Contribution to journalArticle

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