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Silencing of human phosphatidylethanolamine-binding protein 4 sensitizes breast cancer cells to tumor necrosis factor-alpha-induced apoptosis and cell growth arrest.

AbstractPURPOSE:
The current therapeutic approach is not so effective in breast cancer patients. Alternative treatment protocols aimed at different targets need to be explored. We recently reported a novel phosphatidylethanolamine-binding protein, human phosphatidylethanolamine-binding protein 4 (hPEBP4), as an antiapoptotic molecule. The finding led us to explore a promising approach for breast cancer therapy via silencing the expression of hPEBP4.
EXPERIMENTAL DESIGN:
hPEBP4 expression in clinical breast specimens was examined by Tissue Microarrays. RNA interference was used to silence hPEBP4 expression in MCF-7 breast carcinoma cells and the effects on cell proliferation, cell cycle progression, apoptosis, as well as underlying mechanisms, were investigated.
RESULTS:
hPEBP4 was found to be expressed in up to 50% of breast cancers but in only <4% of normal breast tissues. Silencing of hPEBP4 potentiated tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis and cell cycle arrest in MCF-7 cells, which was due to the increased mitogen-activated protein kinase activation and the enhanced phosphatidylethanolamine externalization. Further investigation showed that silencing of hPEBP4 in MCF-7 cells promoted TNF-alpha-induced stability of p53, up-regulation of phospho-p53ser15, p21waf/cip, and Bax, and down-regulation of Bcl-2 and Bcl-xL, which were shown to depend on extracellular signal-regulated kinase 1/2 and c-jun NH2-terminal kinase activation by hPEBP4 silencing. Moreover, the increased proportion of cells in the G0-G1 phase of cell cycle was observed in hPEBP4-silenced MCF-7 cells on TNF-alpha treatment and the expression of cyclin A and cyclin E was down-regulated more significantly.
CONCLUSIONS:
The antiapoptotic effect and the preferential expression pattern in breast cancer tissues make hPEBP4 a new target for breast cancer therapy. Silencing of hPEBP4 expression may be a promising approach for the treatment of breast carcinoma.
AuthorsXiaojian Wang, Nan Li, Hongzhe Li, Bin Liu, Jianming Qiu, Taoyong Chen, Xuetao Cao
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 20 Pg. 7545-53 (Oct 15 2005) ISSN: 1078-0432 [Print] United States
PMID16243830 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cyclin A
  • Cyclin E
  • Phosphatidylethanolamine Binding Protein
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
Topics
  • Apoptosis (drug effects)
  • Blotting, Western
  • Breast Neoplasms (genetics, metabolism, pathology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cyclin A (metabolism)
  • Cyclin E (metabolism)
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Signaling System (drug effects)
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Mitogen-Activated Protein Kinases (metabolism)
  • Phosphatidylethanolamine Binding Protein (genetics, metabolism)
  • Protein Binding
  • Proto-Oncogene Proteins c-raf (metabolism)
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha (pharmacology)
  • Tumor Suppressor Protein p53 (metabolism)
  • Up-Regulation

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