The regulatory mechanism of cell death by rigosertib in diffuse large B-cell lymphoma (DLBCL)

  • 戴 憶涵

Student thesis: Master's Thesis


Diffuse large B-cell lymphoma (DLBCL) the most common lymphoma shows either no response or development of resistance to further treatment in 30% patients Even approximately half of patients are not eligible for high-dose chemotherapy Previous studies report that rigosertib (ON 01910 Na) a multi-kinase inhibitor is selectively cytotoxic for DLBCL and induces more hyperphosphorylation and sumoylation of RanGAP1 in DLBCL cells than in non-neoplastic lymphoblastoid cell line (LCL) Sumoylation is linked to nucleocytoplasmic transport and transcriptional gene repression The exact mechanism of rigosertib-induced cell death in DLBCL remains unclear Our aim was to analyze the efficacy of rigosertib against DLBCL cells in vitro and in vivo and its molecular effects on tumor biology First LCL and DLBCL cells were treated with rigosertib and their viabilities were assessed by the MTT assay We found that rigosertib was selectively cytotoxic and had potential for targeting DLBCL Interestingly rigosertib inhibited nuclear entry of sumoylated proteins RanGAP1 TRAF6 and C-Myb that was confirmed by immunofluoresence Moreover co-immunoprecipitation identified that rigosertib sequestered c-Myb and TRAF6 in the cytoplasm by stimulating their sumoylation through the RanGAP1*SUMO1*Ubc9 pathway Specific knockdown of C-Myb and TRAF6 induced apoptosis and cell cycle arrest Xenograft mice bearing lymphoma cells also exhibited effective tumor regression on rigosertib treatment Thus suppression of c-Myb and TRAF6 activity may be the potential therapeutic targets in DLBCL These data support the clinical development of rigosertib in DLBCL
Date of Award2015 Jul 30
Original languageEnglish
SupervisorKung-Chao Chang (Supervisor)

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