Abstract
BackgroundCurrent therapies for multiple myeloma (MM) are associated with toxicity and resistance, highlighting the need for novel effective therapeutics. Berberine (BBR), a botanical alkaloid derived from several Berberis medicinal plants, has exhibited anti-tumor effects, including against multiple myeloma (MM); however, the molecular mechanism underlying the anti-MM effect has not been previously described. This study aimed to identify the target of berberine and related mechanisms involved in its therapeutic activity against MM.ResultsHere, we demonstrated that BBR treatment killed MM cells in vitro and prolonged the survival of mice bearing MM xenografts in vivo. A screening approach integrating surface plasmon resonance (SPR) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified UHRF1 (ubiquitin-like with PHD and RING Finger domains 1) as a potential target of BBR. Combining molecular docking and SPR analysis, we confirmed UHRF1 as a BBR-binding protein and discovered that BBR binds UHRF1 in the tandem tudor domain and plant homeodomain (TTD-PHD domain). BBR treatment induced UHRF1 degradation via the ubiquitin-dependent proteasome system and reactivated p16INK4A and p73 in MM cells. Overexpression of UHRF1 promoted the MM cell proliferation and rendered MM cells more resistant to BBR, while silencing of UHRF1 with siRNA attenuated BBR-induced cytotoxicity.ConclusionsIn summary, our study has identified UHRF1 as a direct target of BBR and uncovered molecular mechanisms involved in the anti-MM activity of BBR. Targeting UHRF1 through BBR may be a novel therapeutic strategy against MM.
Highlights
Current therapies for multiple myeloma (MM) are associated with toxicity and resistance, highlighting the need for novel effective therapeutics
To assess the potential anti-MM activity of BBR, we investigated its in vitro effects in bone marrow (BM) cells from C57BL/6 J mice, BaF3, SP2/0, and several human MM cell lines at 48 h
Mice myeloma cell SP2/0 and human MM cells were sensitive to treatment with BBR (Fig. 1b)
Summary
Current therapies for multiple myeloma (MM) are associated with toxicity and resistance, highlighting the need for novel effective therapeutics. Multiple myeloma (MM) is an incurable malignant hematological disease, characterized by the abnormal proliferation of clonal plasma cells in the bone marrow [1]. Bortezomib targets the 26S proteasome subunit β5 and exerts anti-MM effects by inhibiting the secretion of interleukin-6 (IL-6) through the NF-κB signaling pathway. It can block the turnover of poly-ubiquitinated proteins through the ubiquitinproteasome system [4, 5]. Toxicities associated with global proteasomal inhibition and resistance to bortezomib are major concerns in MM, prompting the discovery of new agents and development of more effective therapies for the treatment of MM
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