Reciprocal protection of Mcl-1 and Bim from ubiquitin-proteasome degradation

Wuillème-Toumi, Soraya; Trichet, Valérie; Gomez‐Bougie, Patricia; Gratas, Catherine; Bataille, Régis; Amiot, Martine

doi:10.1016/j.bbrc.2007.07.070

Cited by 29 publications

(25 citation statements)

References 26 publications

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“…We identified a role of Bim on Mcl-1 up-regulation, which were in agreement with the previous findings. Wuilleme-Toumi et al have reported that Bim induces Mcl-1 increase by inhibiting its ubiquitination (26). In our studies, the turning point for Mcl-1 level change was 18 h upon S1 treatment.…”

Section: Discussionsupporting

confidence: 59%

S1, a Novel Pan-BH3 Mimetic, Induces Apoptosis in Mcl-1-Overexpressing Cells Through Bak

et al. 2012

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Abstract. Mcl-1, an anti-apoptotic Bcl-2 homolog that has a structurally divergent BH3-binding pocket, non-redundant action model, and unique characteristic of short life confers complete resistance to the BH3 mimetic ABT-737. Herein, we used S1, previously identified as a Mcl-1/Bcl-2 dual inhibitor and a pure BH3 mimetic, to explore the mechanism of Mcl-1's action and supply a strategy to challenge Mcl-1's protection. Apoptosis assay in SMMC-7721, HCT116, and K562 cells demonstrated that S1 can effectively challenge Mcl-1's anti-apoptotic effect. Notably, we discovered an unexpected dynamic change of Mcl-1 that directly correlates with resistance or commitment to apoptosis induced by both ABT-737 and S1. Co-immunoprecipitation assays demonstrated that Mcl-1 increase results from Bim trafficking from Bcl-2 to Mcl-1, while subsequent Bak released by S1 determines Mcl-1 decrease and full-blown apoptosis. Further experiments using Bak shRNA testified that Bak accounts for S1-induced apoptosis and Mcl-1 decrease. Consistently, Bax-deficient DU145 cells are sensitive to S1, whereas Bak-mutant MKN-28 cells are significantly more resistant. The in vitro model could be extended to an in vivo mouse xenograft model in which Mcl-1 confers resistance by increased protein level, and the release of Bak could serve as a biomarker of apoptosis.[Supplementary materials: available only at http://dx

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Section: Discussionsupporting

confidence: 59%

S1, a Novel Pan-BH3 Mimetic, Induces Apoptosis in Mcl-1-Overexpressing Cells Through Bak

et al. 2012

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“…4B). This accumulation of Bim EL may be the result of the accumulation of Mcl-1, which binds to Bim EL in cytoplasm (36,37). Although recent studies have identified Gal-3 as the substrate of c-Abl in solid cancers (38,39), Gal-3 expression was not reduced by TKI in MYL and MYL/G3 (Fig.…”

Section: Molecular Sequelae Following Gal-3 Overexpression In Leukemicmentioning

confidence: 91%

Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia

Yamamoto-Sugitani

Kuroda

Ashihara

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Bone marrow (BM) microenvironment (BMME) constitutes the sanctuary for leukemic cells. In this study, we investigated the molecular mechanisms for BMME-mediated drug resistance and BM lodgment in chronic myelogenous leukemia (CML). Gene-expression profile as well as signal pathway and protein analyses revealed that galectin-3 (Gal-3), a member of the β-gal–binding galectin family of proteins, was specifically induced by coculture with HS-5 cells, a BM stroma cell-derived cell line, in all five CML cell lines examined. It was also found that primary CML cells expressed high levels of Gal-3 in BM. Enforced expression of Gal-3 activated Akt and Erk, induced accumulation of Mcl-1, and promoted in vitro cell proliferation, multidrug resistance to tyrosine kinase inhibitors for Bcr-Abl and genotoxic agents as a result of impaired apoptosis induction, and chemotactic cell migration to HS-5–derived soluble factors in CML cell lines independently of Bcr-Abl tyrosine kinase. The conditioned medium from Gal-3–overexpressing CML cells promoted in vitro cell proliferation of CML cells and HS-5 cells more than did the conditioned medium from parental cells. Moreover, the in vivo study in a mice transplantation model showed that Gal-3 overexpression promoted the long-term BM lodgment of CML cells. These results demonstrate that leukemia microenvironment-specific Gal-3 expression supports molecular signaling pathways for disease maintenance in BM and resistance to therapy in CML. They also suggest that Gal-3 may be a candidate therapeutic target to help overcome BMME-mediated therapeutic resistance.

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“…22 Overexpression of any prosurvival Bcl-2 family protein caused the accumulation of Bim in nontransformed as well as malignant lymphoid cells, confirming that the formation of complexes with prosurvival proteins is an important mechanism regulating the steady state level of Bim. 41,42 We show that Bcl-2/Bim complexes are highly susceptible to disruption by ABT-737, and that the released Bim then binds to Mcl-1. It is also conceivable that some of the Bim released from Bcl-2 also directly activates Bax or Bak.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2, Bcl-xL, and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells

Mérino

Khaw

Glaser

et al. 2012

Blood

171

152

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The BH3-mimetic ABT-737 and an orally bioavailable compound of the same class, navitoclax (ABT-263), have shown promising antitumor efficacy in preclinical and early clinical studies. Although both drugs avidly bind Bcl-2, Bcl-x L , and Bcl-w in vitro, we find that Bcl-2 is the critical target in vivo, suggesting that patients with tumors overexpressing Bcl-2 will probably benefit. In human non-Hodgkin lymphomas, high expression of Bcl-2 but not Bcl-x L predicted sensitivity to ABT-263. Moreover, we show that increasing Bcl-2 sensitized normal and transformed lymphoid cells to ABT-737 by elevating proapoptotic Bim. In striking contrast, increasing Bcl-x L or Bcl-w conferred robust resistance to ABT-737, despite also increasing Bim. Cell-based protein redistribution assays unexpectedly revealed that ABT-737 disrupts Bcl-2/Bim complexes more readily than Bcl-x L /Bim or Bcl-w/Bim complexes. These results have profound implications for how BH3-mimetics induce apoptosis and how the use of these compounds can be optimized for treating lymphoid malignancies. (Blood. 2012;119(24):5807-5816) IntroductionDefects in the mitochondrial apoptotic pathway regulated by the Bcl-2 family of proteins play a major role in cancer development and in conferring chemoresistance. 1 Within the family, Bax and Bak are essential for mitochondrial membrane permeabilization and cell death. 2 Prosurvival proteins (Bcl-2, Bcl-x L , Bcl-w, Mcl-1, A1) oppose Bax and Bak and ensure mitochondrial integrity and cell survival. 1 These prosurvival proteins also interact with distant relatives that share only 1 Bcl-2 Homology region, BH3, that is critical for their proapoptotic function. The BH3-only proteins such as Bim, Bad, Puma, and Noxa act as stress sensors and relieve the inhibition of Bax and Bak by the prosurvival proteins.The clinical efficacy of most anticancer therapeutics primarily reflects their ability to induce apoptosis. Resistance to conventional anticancer therapeutics (eg, etoposide) is often because of a failure to activate BH3-only proteins, for example because of mutation of the tumor suppressor p53, which is critical for transcriptional induction of Puma and Noxa after DNA damage. 3 Overexpression of prosurvival Bcl-2 proteins, or silencing of BH3-only protein expression, are also associated with inferior therapeutic outcomes. 4,5 BH3-mimetic drugs, such as ABT-737, were developed to directly counter such apoptotic blocks. ABT-737 binds avidly to Bcl-2, Bcl-x L , and Bcl-w, but not Mcl-1 or A1. 6,7 In preclinical studies, it demonstrated single agent efficacy against tumors with low Mcl-1 or A1 levels, such as follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and small cell lung carcinoma (SCLC). ABT-737 shows limited toxicity toward normal cells, although there is transient reduction of platelets and lymphocytes. 6,8 , an orally bioavailable compound in the same class with similar target specificity, also exhibited efficacy in various cancer-derived cell lines both in vitro and in vivo, 6,9,10 and is undergoing p...

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Reciprocal protection of Mcl-1 and Bim from ubiquitin-proteasome degradation

Cited by 29 publications

References 26 publications

S1, a Novel Pan-BH3 Mimetic, Induces Apoptosis in Mcl-1-Overexpressing Cells Through Bak

S1, a Novel Pan-BH3 Mimetic, Induces Apoptosis in Mcl-1-Overexpressing Cells Through Bak

Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia

Bcl-2, Bcl-xL, and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells

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