The Stress Protein BAG3 Stabilizes Mcl-1 Protein and Promotes Survival of Cancer Cells and Resistance to Antagonist ABT-737

Boiani, Mariana; Daniel, Cristina; Liu, Xueyuan; Hogarty, Michael D.; Marnett, Lawrence J.

doi:10.1074/jbc.m112.414177

Cited by 66 publications

(59 citation statements)

References 66 publications

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“…We found that ABT737 alone or in combination with paclitaxel had little effect on ES2 cell viability (Fig. 4B), which is consistent with earlier reports showing that Mcl-1 mediates ABT737 resistance (11,22,29,30).…”

Section: Mcl-1-specific High-affinity Antagonist Mim1 Increases Sensisupporting

confidence: 82%

“…In addition to the BAG domain, BAG3 contains a WW domain near its N-terminus and a proline-rich region (multiple PXXP motifs) (16,17), and our earlier study showed that BAG3 also regulates cell motility and tumor growth, invasion and metastasis (18). Moreover, several lines of evidence indicate that downregulation of BAG3 enhances chemotherapy-mediated apoptosis among cancer cells (19)(20)(21), which is consistent with the recent finding that BAG3 stabilizes Mcl-1, Bcl-2 and Bcl-X L , thereby promoting cancer cell survival (22,23). The precise mechanism by which BAG3 exerts these effects remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer

Habata

Iwasaki

Sugio

et al. 2016

International Journal of Oncology

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Abstract. Paclitaxel in combination with carboplatin improves survival among patients with susceptible ovarian cancers, but no strategy has been established against resistant ovarian cancers. BAG3 (Bcl-2-associated athanogene 3) is one of six BAG family proteins, which are involved in such cellular processes as proliferation, migration and apoptosis. In addition, expression of BAG3 with Mcl-1, a Bcl-2 family protein, reportedly associates with resistance to chemotherapy. Our aim in this study was to evaluate the functional role of BAG3 and Mcl-1 in ovarian cancer chemoresistance and explore possible new targets for treatment. We found that combined expression of BAG3 and Mcl-1 was significantly associated with a poor prognosis in ovarian cancer patients. In vitro, BAG3 knockdown in ES2 clear ovarian cancer cells significantly increased the efficacy of paclitaxel in combination with the Mcl-1 antagonist MIM1, with or without the Bcl-2 family antagonist ABT737. Moreover, BAG3 was found to positively regulate Mcl-1 levels by binding to and inhibiting USP9X. Our data show that BAG3 and Mcl-1 are key mediators of resistance to chemotherapy in ovarian cancer. In BAG3 knockdown ES2 clear ovarian cancer cells, combination with ABT737 and MIM1 enhanced the efficacy of paclitaxel. These results suggest that inhibiting BAG3 in addition to antiapoptotic Bcl-2 family proteins may be a useful therapeutic strategy for the treatment of chemoresistant ovarian cancers.

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Section: Mcl-1-specific High-affinity Antagonist Mim1 Increases Sensisupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer

Habata

Iwasaki

Sugio

et al. 2016

International Journal of Oncology

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“…Thus, it can be simply speculated that, with deficiency of BIS, BAG1 may replace BIS in the formation of complex with HSP70 and facilitate the proteasome-dependent degradation of SOD, resulting in impaired induction of SOD1 or SOD2 expression. Supporting this idea, BIS has been recently reported to stabilise myeloid cell leukaemia sequence 1 (BCL2-related) (MCL-1), preventing its HSP70-dependent degradation [40]. However, the constitutive expression of SOD1, as well as SOD2, was higher in BIS-HT mice than in BIS-WT mice before induction of diabetes, which correlates with basal SOD activity.…”

Section: Discussionmentioning

confidence: 74%

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

et al. 2013

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Aims/hypothesis B cell CLL/lymphoma 2 (BCL-2)-interacting cell death suppressor (BIS), known as an anti-stress and antiapoptotic protein, has been reported to modulate susceptibility to oxidative stress. This study investigated the potential role of BIS as an antioxidant protein in diabetic nephropathy. Methods Diabetes was induced in BIS-heterozygote (BIS-HT) mice via streptozotocin injections and the resulting phenotypes were compared with those of BIS-wild-type (BIS-WT) mice over the 20 weeks following diabetes induction.Results Renal injuries, represented by increased plasma creatinine levels and increased albuminuria, were greater in diabetic BIS-HT mice than in diabetic BIS-WT mice, and were accompanied by a significant increase in reactive oxygen species (ROS) and oxidative stress markers. Moreover, renal pathological changes and the apoptotic process were accelerated in diabetic BIS-HT mice compared with diabetic BIS-WT mice with the same degree of hyperglycaemia; all were restored by 4-hydroxy-2,2,6,6-tetramethylpiperidine-Noxyl (tempol) treatment. The levels of NADPH oxidase and related proteins were not significantly higher in diabetic BIS-HT mice compared with diabetic BIS-WT mice. However, levels of superoxide dismutase (SOD)1 and SOD2 increased on the induction of diabetes in BIS-WT mice but not in BIS-HT mice, correlating with the total SOD activity. An in vitro study showed that knockdown of BIS production also resulted in impaired induction of SOD activity as well as SOD levels in HK-2 and NMS cells, concomitant with significant ROS accumulation. Conclusion/interpretation Our results suggest that the decreased antioxidant capacity of BIS aggravates diabetic nephropathy in diabetic BIS-HT mice, possibly as a result of the disruption in the regulation of SOD protein quality under oxidative stress. Electronic supplementary material The online version of this article (doi:10.1007/s00125-013-3064-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…However, ABT-263 and ABT-737 are unable to bind Mcl-1. Therefore, Mcl-1 is not inhibited by ABT-263 or ABT-737 and is considered to be a major factor in resistance to ABT-737 (15,41,42). Furthermore, the amplification of the Mcl-1 locus is the most frequent somatic genetic event in human cancer (18).…”

Section: Discussionmentioning

confidence: 99%

The Natural Compound Cantharidin Induces Cancer Cell Death through Inhibition of Heat Shock Protein 70 (HSP70) and Bcl-2-associated Athanogene Domain 3 (BAG3) Expression by Blocking Heat Shock Factor 1 (HSF1) Binding to Promoters

Kim

Kwon

et al. 2013

Journal of Biological Chemistry

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Background: HSF1 is a transcription factor that enhances cancer formation and progression. Results: Cantharidin inhibited the binding of HSF1 to the HSP70 promoter and subsequently blocked HSF1-dependent HSP70 expression. Conclusion:The HSF1-dependent expression of HSP70 and BAG3 is inhibited by cantharidin, causing the down-regulation of antiapoptotic BCL-2 family proteins, especially MCL-1. Significance: This information provides a new target molecule and pathway of cantharidin.

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The Stress Protein BAG3 Stabilizes Mcl-1 Protein and Promotes Survival of Cancer Cells and Resistance to Antagonist ABT-737

Cited by 66 publications

References 66 publications

BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer

BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

The Natural Compound Cantharidin Induces Cancer Cell Death through Inhibition of Heat Shock Protein 70 (HSP70) and Bcl-2-associated Athanogene Domain 3 (BAG3) Expression by Blocking Heat Shock Factor 1 (HSF1) Binding to Promoters

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