Targeting beta-transducin repeat-containing protein E3 ubiquitin ligase augments the effects of antitumor drugs on breast cancer cells.

Abstract

beta-Transducin repeat-containing proteins (beta-TrCP) serve as substrate recognition component of E3 ubiquitin ligases that control stability of important regulators of cell cycle and signal transduction. beta-TrCP function is essential for the induction of nuclear factor kappaB transcriptional activities, which play a key role in proliferation and survival of cancer cells and are often constitutively up-regulated in human breast cancers. Here we show that inhibition of beta-TrCP either by RNAi approach or by forced expression of a dominant-negative beta-TrCP mutant suppresses growth and survival of human breast cancer cells. In addition, inhibition of beta-TrCP augments the antiproliferative effects of anticancer drugs such as doxorubicin, tamoxifen, and paclitaxel on human mammary tumor cells. These data provide the proof of principle that targeting beta-TrCP might be beneficial for anticancer therapies.

• Authors: Weigang Tang, Ying Li, Duonan Yu, Andrei Thomas-Tikhonenko, Vladimir S Spiegelman, Serge Y Fuchs
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 5 Pg. 1904-8 (Mar 01 2005) ISSN: 0008-5472 [Print] United States
• PMID: 15753389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• RNA, Small Interfering
• beta-Transducin Repeat-Containing Proteins
• Tamoxifen
• Doxorubicin
• Ubiquitin-Protein Ligases
• Paclitaxel

Topics

• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• Breast Neoplasms (genetics)
• Colony-Forming Units Assay
• Doxorubicin (therapeutic use)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic
• Genes, Dominant
• Humans
• Mutation (genetics)
• Paclitaxel (therapeutic use)
• RNA, Small Interfering (pharmacology)
• Tamoxifen (therapeutic use)
• Tumor Cells, Cultured
• Ubiquitin-Protein Ligases (antagonists & inhibitors, genetics, metabolism)
• beta-Transducin Repeat-Containing Proteins (antagonists & inhibitors, genetics, metabolism)