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Experimental and Molecular Therapeutics

Potentiation of UCN-01 lethality by MEK1/2 inhibitors in human multiple myeloma cells involves modulation of Bim phosphorylation and degradation

Xin-Yan Pei, Yun Dai, Sarah Tenorio, Hisashi Harada, Jianghua Lu, Paul Dent and Steven Grant
Xin-Yan Pei
Virginia Commonwealth University and Massey Cancer Center, Richmond, VA
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Yun Dai
Virginia Commonwealth University and Massey Cancer Center, Richmond, VA
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Sarah Tenorio
Virginia Commonwealth University and Massey Cancer Center, Richmond, VA
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Hisashi Harada
Virginia Commonwealth University and Massey Cancer Center, Richmond, VA
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Jianghua Lu
Virginia Commonwealth University and Massey Cancer Center, Richmond, VA
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Paul Dent
Virginia Commonwealth University and Massey Cancer Center, Richmond, VA
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Steven Grant
Virginia Commonwealth University and Massey Cancer Center, Richmond, VA
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DOI:  Published May 2007
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AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

Abstract

3210

In previous studies, our group reported that exposure of human myeloma, leukemia, and solid tumor cells to the PKC and Chk1 inhibitor UCN-01 induced the marked activation of MEK1/2/ERK1/2. Furthermore, prevention of MEK1/2/ERK1/2 activation (e.g., by pharmacologic MEK1/2 inhibitors) dramatically increased apoptosis in UCN-01-treated cells, suggesting that UCN-01-mediated MEK1/2/ERK1/2 activation represents a cytoprotective response. However, the downstream target(s) of MEK1/2/ERK1/2 signaling in this setting remains unclear. Among numerous possibilities, recent attention has focused on post-translational regulation of Bim, an “activator” BH3-only protein, by ERK1/2. Consequently, modulation of Bim phosphorylation and its functional role in cell death induced by UCN-01 ± MEK1/2 inhibitors (e.g., PD184352) was examined. Exposure (8-24h) of U266 cells to UCN-01 dramatically induced Bim phosphorylation and degradation, associated with ERK1/2 activation. These events were largely blocked by co-administration of PD184352, resulting in accumulation of unphosphorylated Bim and a marked increase in caspase-3 activation and PARP degradation. Identical events occurred in RPMI8226 cells. Enforced activation of ERK1/2 by stable transfection with constitutively active (CA)-MEK1 increased Bim phosphorylation/degradation, which was further enhanced by UCN-01 exposure. Ectopic expression of CA-MEK1 diminished the inhibitory effects of PD98059 but not PD184352 on UCN-01-mediated ERK1/2 activation and Bim phosphorylation, as well as caspase-3 cleavage. Knockdown of Bim by transient or stable transfection with a construct encoding shRNA directed against Bim diminished the lethality of the UCN-01/MEK1/2 inhibitor regimen without modifying ERK1/2 inactivation. Co-immunoprecipitation analysis revealed that exposure to UCN-01 markedly decreased binding of Bim to Bcl-2 and Bcl-xL. These events were reversed by co-administration of PD184352, resulting in conformational change of Bax/Bak and Bax translocation. Ectopic expression of Bcl-xL sequestered Bim and blunted the lethality of the UCN-01/MEK1/2 inhibitor regimen, without modulating Bim phosphorylation. Similar results were observed in cells overexpressing Bcl-2. Lastly, treatment with PD184352 either alone or in combination with UCN-01 diminished IL-6- or IGF-1-induced ERK1/2 activation and Bim phosphorylation, potentially accounting for failure of these survival factors to protect myeloma cells from the lethality of this combinational regimen. These studies indicate that Bim represents a critical downstream target of MEK1/2/ERK1/2 in cells exposed to UCN-01 and that Bim activation contributes to synergism between UCN-01 and MEK1/2 inhibitors.

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  • 98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

  • American Association for Cancer Research
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Cancer Research: 67 (9 Supplement)
May 2007
Volume 67, Issue 9 Supplement
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Potentiation of UCN-01 lethality by MEK1/2 inhibitors in human multiple myeloma cells involves modulation of Bim phosphorylation and degradation
Xin-Yan Pei, Yun Dai, Sarah Tenorio, Hisashi Harada, Jianghua Lu, Paul Dent and Steven Grant
Cancer Res May 1 2007 (67) (9 Supplement) 3210;

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Potentiation of UCN-01 lethality by MEK1/2 inhibitors in human multiple myeloma cells involves modulation of Bim phosphorylation and degradation
Xin-Yan Pei, Yun Dai, Sarah Tenorio, Hisashi Harada, Jianghua Lu, Paul Dent and Steven Grant
Cancer Res May 1 2007 (67) (9 Supplement) 3210;
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