BCL-2 family regulation by the 20S proteasome inhibitor bortezomib

Fennell, Dean A.; Chacko, Alex; Mutti, Luciano

doi:10.1038/sj.onc.1210744

Cited by 135 publications

(115 citation statements)

References 121 publications

(139 reference statements)

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“…This process may considerably enhance the efficiency of the 'three-at-once' bortezomib-induced stabilization of the BH3-only proteins NOXA, BIK and BIM, in activating BAX/BAK complexes and inducing mitochondrial collapse. 42,43 This hypothesis remain to be confirmed, keeping in mind that, additional factors, other than BIM, BAX and BAK proteins, may account for GX15-070 to allow cell sensitization to bortezomib, such as the activation of the G 2 cell-cycle checkpoint by both agents. 26,44 In conclusion, the present study demonstrates that GX15-070 efficiently kills CLL cells and that high levels of BCL-2 phosphorylation at Ser70, due to MEK1/ERK pathway activation of CLL cells, reduce its activity and synergism with the proteasome inhibitor bortezomib.…”

Section: Discussionmentioning

confidence: 99%

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

et al. 2008

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Chronic lymphocytic leukemia (CLL) is a B-cell lymphoid neoplasm with deregulated apoptosis and overexpression of several antiapoptotic BCL-2 proteins. GX15-070/Obatoclax is a small-molecule BH3 mimetic compound that has shown activity against several hematologic malignancies and solid tumors. In the present work, we report that GX15-070 led to the disruption of BCL-2/BIM and MCL-1/BAK complexes in CLL cells, followed by the activation of the mitochondrial apoptotic pathway. CLL cells showed lower sensitivity to GX15-070 than primary mantle cell lymphoma (MCL) ones, in correlation with higher levels of phosphorylated BCL-2 at serine 70 residue (pBCL-2(Ser70)) in CLL cells. Decrease in BCL-2 phosphorylation by extracellular signal-regulated kinase (ERK)1/2 inhibition increased CLL sensitivity to GX15-070, while blocking BCL-2 dephosphorylation using a PP2A antagonist reduced the activity of this BH3 mimetic. GX15-070 activity was increased by cotreatment with the proteasome inhibitor bortezomib. However, as proteasome inhibition led to the accumulation of phosphorylated BCL-2, the degree of interaction between GX15-070 and bortezomib was regulated by basal pBCL-2(Ser70) levels. These results support the role of BCL-2 phosphorylation as a mechanism of resistance to BH3 mimetic compounds, and demonstrate that combination approaches including ERK inhibitors could enhance BH3 mimetics activity both alone or in combination with proteasome inhibitors.

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Section: Discussionmentioning

confidence: 99%

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

et al. 2008

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“…Bortezomib was originally developed as a proteasome inhibitor, which blocked the degradation of ubiquitinated IkBa, a negative regulator of the canonical nuclear factor (NF)-kB pathway, and prevented its translocation into the nucleus. 5 However, several investigators have proposed additional mechanisms for its antitumor effects, especially focusing on the expression of BH3-only proteins, including Noxa, Bid, puma and Bik, [6][7][8][9] and on misfolded protein accumulation followed by endoplasmic reticulum(ER) stressassociated apoptosis. 10,11 When proteasome function is inhibited, damaged proteins including unfolded or oxidatively modified proteins accumulate in the intracellular environment, which causes ER overload, well recognized as an ER stress.…”

Section: Introductionmentioning

confidence: 99%

Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress

et al. 2010

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“…The proteasome is responsible for the selective degradation of misfolded and high-turnover proteins. 7,8 Therefore, both normal and malignant plasma cells are highly susceptible to proteasome inhibition. 9 Apoptosis is induced when the proteasome is inhibited in part because of an accumulation of misfolded proteins which, leads to endoplasmic reticulum stress and the unfolded protein response.…”

Section: Introductionmentioning

confidence: 99%

Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma

Ponder

Matulis

Hitosugi

et al. 2016

Cancer Biology & Therapy

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Carfilzomib (Kyprolis Ò ), a second generation proteasome inhibitor, is FDA approved for single-agent use among relapsed/refractory multiple myeloma (MM). To enhance the therapeutic efficacy of carfilzomib, we sought to combine carfilzomib with other novel agents. TG02, a multi-kinase inhibitor, targets JAK2 and CDK9. The rationale for co-treatment with carfilzomib and TG02 is that both independently target Mcl-1 and most myeloma cells are dependent on this anti-apoptotic protein for survival. We observed at least additive effects using the combination treatment in MM cell lines and patient samples. To determine how the bone marrow environment affects the efficacy of the combination we conducted co-culture experiments with Hs-5 stromal cells. We also examined the mechanism of increased apoptosis by determining the affect on expression of the Bcl-2 family of proteins. We found that carfilzomib increases NOXA mRNA expression, as expected, and TG02 treatment caused a decrease in Mcl-1 protein but not mRNA levels. Consistent with this possibility, we find silencing CDK9 does not change carfilzomib sensitivity in the same manner as addition of TG02. Since changes in Mcl-1 protein occur in the presence of a proteasome inhibitor we hypothesize that regulation of Mcl-1 translation is the most likely mechanism. Taken together our data suggest that dual inhibition of Mcl-1 via decreased expression and the induction of its antagonist NOXA by the combination of carfilzomib and TG02 is active in myeloma and warrants further testing preclinically and in clinical trials. Moreover, regulation of Mcl-1 by TG02 is more complex than initially appreciated.

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BCL-2 family regulation by the 20S proteasome inhibitor bortezomib

Cited by 135 publications

References 121 publications

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress

Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma

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