ON 01910.Na inhibits growth of diffuse large B-cell lymphoma by cytoplasmic sequestration of sumoylated C-MYB/TRAF6 complex

Yi Han Dai, Liang-Yi Hung, Ruo Yu Chen, Chien Hsien Lai, Kung-Chao Chang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, shows either no response or development of resistance to further treatment in 30% of the patients that warrants the development of novel drugs. We have reported that ON 01910.Na (rigosertib), a multikinase inhibitor, is selectively cytotoxic for DLBCL and induces more hyperphosphorylation and sumoylation of Ran GTPase-activating protein 1 (RanGAP1) in DLBCL cells than in non-neoplastic lymphoblastoid cell line. However, the exact mechanism of rigosertib-induced cell death in DLBCL remains to be clarified. Here, we analyzed the efficacy of rigosertib against DLBCL cells in vitro and in vivo and its molecular effects on tumor biology. We found for the first time that rigosertib attenuated expression of unmodified and sumoylated tumor necrosis factor receptor–associated factor 6 (TRAF6) and c-Myb and inhibited nuclear entry of sumoylated RanGAP1, TRAF6, and c-Myb that was confirmed by immunofluorescence. Moreover, co-immunoprecipitation showed that rigosertib induced sequestration of 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 tumor cell apoptosis and cell cycle arrest at G1 phase. Xenograft mice bearing lymphoma cells also exhibited effective tumor regression on rigosertib treatment along with cytoplasmic expression of c-Myb and TRAF6. Nuclear expression of c-Myb in clinical cases of DLBCL correlated with a poor prognosis. Thus, suppression of c-Myb and TRAF6 activity may have therapeutic implication in DLBCL. These data support the clinical development of rigosertib in DLBCL.

Original languageEnglish
Pages (from-to)129-143.e13
JournalTranslational Research
Volume175
DOIs
Publication statusPublished - 2016 Sep 1

Fingerprint

TNF Receptor-Associated Factor 6
Lymphoma, Large B-Cell, Diffuse
Cells
ran GTP-Binding Protein
Growth
GTPase-Activating Proteins
Sumoylation
Tumors
Lymphoma
Bearings (structural)
Neoplasms
ON 01910
G1 Phase
Cell death
Cell Cycle Checkpoints
Immunoprecipitation
Heterografts
Fluorescent Antibody Technique
Cytoplasm
Cell Death

All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical
  • Physiology (medical)

Cite this

@article{28830b2410c043fcbf7d3bb24038f106,
title = "ON 01910.Na inhibits growth of diffuse large B-cell lymphoma by cytoplasmic sequestration of sumoylated C-MYB/TRAF6 complex",
abstract = "Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, shows either no response or development of resistance to further treatment in 30{\%} of the patients that warrants the development of novel drugs. We have reported that ON 01910.Na (rigosertib), a multikinase inhibitor, is selectively cytotoxic for DLBCL and induces more hyperphosphorylation and sumoylation of Ran GTPase-activating protein 1 (RanGAP1) in DLBCL cells than in non-neoplastic lymphoblastoid cell line. However, the exact mechanism of rigosertib-induced cell death in DLBCL remains to be clarified. Here, we analyzed the efficacy of rigosertib against DLBCL cells in vitro and in vivo and its molecular effects on tumor biology. We found for the first time that rigosertib attenuated expression of unmodified and sumoylated tumor necrosis factor receptor–associated factor 6 (TRAF6) and c-Myb and inhibited nuclear entry of sumoylated RanGAP1, TRAF6, and c-Myb that was confirmed by immunofluorescence. Moreover, co-immunoprecipitation showed that rigosertib induced sequestration of 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 tumor cell apoptosis and cell cycle arrest at G1 phase. Xenograft mice bearing lymphoma cells also exhibited effective tumor regression on rigosertib treatment along with cytoplasmic expression of c-Myb and TRAF6. Nuclear expression of c-Myb in clinical cases of DLBCL correlated with a poor prognosis. Thus, suppression of c-Myb and TRAF6 activity may have therapeutic implication in DLBCL. These data support the clinical development of rigosertib in DLBCL.",
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ON 01910.Na inhibits growth of diffuse large B-cell lymphoma by cytoplasmic sequestration of sumoylated C-MYB/TRAF6 complex. / Dai, Yi Han; Hung, Liang-Yi; Chen, Ruo Yu; Lai, Chien Hsien; Chang, Kung-Chao.

In: Translational Research, Vol. 175, 01.09.2016, p. 129-143.e13.

Research output: Contribution to journalArticle

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T1 - ON 01910.Na inhibits growth of diffuse large B-cell lymphoma by cytoplasmic sequestration of sumoylated C-MYB/TRAF6 complex

AU - Dai, Yi Han

AU - Hung, Liang-Yi

AU - Chen, Ruo Yu

AU - Lai, Chien Hsien

AU - Chang, Kung-Chao

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AB - Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, shows either no response or development of resistance to further treatment in 30% of the patients that warrants the development of novel drugs. We have reported that ON 01910.Na (rigosertib), a multikinase inhibitor, is selectively cytotoxic for DLBCL and induces more hyperphosphorylation and sumoylation of Ran GTPase-activating protein 1 (RanGAP1) in DLBCL cells than in non-neoplastic lymphoblastoid cell line. However, the exact mechanism of rigosertib-induced cell death in DLBCL remains to be clarified. Here, we analyzed the efficacy of rigosertib against DLBCL cells in vitro and in vivo and its molecular effects on tumor biology. We found for the first time that rigosertib attenuated expression of unmodified and sumoylated tumor necrosis factor receptor–associated factor 6 (TRAF6) and c-Myb and inhibited nuclear entry of sumoylated RanGAP1, TRAF6, and c-Myb that was confirmed by immunofluorescence. Moreover, co-immunoprecipitation showed that rigosertib induced sequestration of 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 tumor cell apoptosis and cell cycle arrest at G1 phase. Xenograft mice bearing lymphoma cells also exhibited effective tumor regression on rigosertib treatment along with cytoplasmic expression of c-Myb and TRAF6. Nuclear expression of c-Myb in clinical cases of DLBCL correlated with a poor prognosis. Thus, suppression of c-Myb and TRAF6 activity may have therapeutic implication in DLBCL. These data support the clinical development of rigosertib in DLBCL.

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