A dominant-negative F-box deleted mutant of E3 ubiquitin ligase, β-TrCP1/FWD1, markedly reduces myeloma cell growth and survival in mice

Ramaswamy Sharma, Paul J. Williams, Anjana Gupta, Brandon McCluskey, Shylesh Bhaskaran, Steve Muñoz, Babatunde O. Oyajobi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Treatment of multiple myeloma with bortezomib can result in severe adverse effects, necessitating the development of targeted inhibitors of the proteasome. We show that stable expression of a dominant-negative F-box deleted (ΔF) mutant of the E3 ubiquitin ligase, SCFβ-TrCP/FWD1, in murine 5TGM1 myeloma cells dramatically attenuated their skeletal engraftment and survival when inoculated into immunocompetent C57BL/KaLwRij mice. Similar results were obtained in immunodeficient bg-nuxid mice, suggesting that the observed effects were independent of host recipient immune status. Bone marrow stroma offered no protection for 5TGM1-ΔF cells in cocultures treated with tumor necrosis factor (TNF), indicating a cell-autonomous anti-myeloma effect. Levels of p100, IκBa, Mcl-1, ATF4, total and cleaved caspase-3, and phospho-β-catenin were elevated in 5TGM1-ΔF cells whereas cIAP was downregulated. TNF also activated caspase-3 and downregulated Bcl-2, correlating with the enhanced susceptibility of 5TGM1-ΔF cells to apoptosis. Treatment of 5TGM1 tumorbearing mice with a β-TrCP1/FWD1 inhibitor, pyrrolidine dithiocarbamate (PDTC), significantly reduced tumor burden in bone. PDTC also increased levels of cleaved Mcl-1 and caspase-3 in U266 human myeloma cells, correlating with our murine data and validating the development of specific β-TrCP inhibitors as an alternative therapy to nonspecific proteasome inhibitors for myeloma patients.

Original languageEnglish (US)
Pages (from-to)21589-21602
Number of pages14
JournalOncotarget
Volume6
Issue number25
DOIs
StatePublished - 2015

Keywords

  • 5TGM1
  • FWD1/β-TrCP1
  • Myeloma
  • Plasmacytoma
  • Proteasome

ASJC Scopus subject areas

  • Oncology

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