Targeting beta-transducin repeat-containing protein E3 ubiquitin ligase augments the effects of antitumor drugs on breast cancer cells.
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.
Tang
Weigang
W
Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6046, USA.
Li
Ying
Y
Yu
Duonan
D
Thomas-Tikhonenko
Andrei
A
Spiegelman
Vladimir S
VS
Fuchs
Serge Y
SY
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics*; D003114:Colony-Forming Units Assay; D004317:Doxorubicin / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006801:Humans; D009154:Mutation / Q000235:genetics; D017239:Paclitaxel / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D013629:Tamoxifen / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D044844:beta-Transducin Repeat-Containing Proteins; D013629:Tamoxifen; D004317:Doxorubicin; D044767:Ubiquitin-Protein Ligases; D017239:Paclitaxel