Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins

Hockings, Colin; Alsop, Amber E.; Fennell, Stephanie; Lee, Erinna F.; Fairlie, W. Douglas; Dewson, Grant; Kluck, Ruth M.

doi:10.1038/s41418-017-0010-6

Cited by 51 publications

(44 citation statements)

References 60 publications

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“…In the present study, we report that the AMPK-Mfn1 pathway is closely regulated by resveratrol. 74,75 This finding provides an easy and effective approach to activate protective the AMPK-Mfn1 pathway in the setting of cerebral IR injury. 76…”

Section: Discussionmentioning

confidence: 88%

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Gao

Wang

et al. 2019

Int J Experimental Path

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Summary The pathogenesis of cerebral ischaemia reperfusion injury (IRI) has not been fully described. Accordingly, there is little effective drug available for the treatment of cerebral IRI. The aim of our study was to explore the exact role played by Mfn1‐mediated mitochondrial protection in cerebral IRI and evaluate the beneficial action of resveratrol on reperfused brain. Our study demonstrated that hypoxia‐reoxygenation (HR) injury caused N2a cell apoptosis and this process was highly affected by mitochondrial dysfunction. Decreased mitochondrial membrane potential, increased mitochondrial oxidative stress, and an activated mitochondrial apoptosis pathway were noted in HR‐treated N2a cells. Interestingly, resveratrol treatment could attenuate N2a cell apoptosis via sustaining mitochondrial homeostasis. Further, we found that resveratrol modulated mitochondrial performance via activating the Mfn1‐related mitochondrial protective system. Knockdown of Mfn1 could abolish the beneficial effects of resveratrol on HR‐treated N2a cells. Besides, we also report that resveratrol regulated Mfn1 expression via the AMPK pathway; inhibition of AMPK pathway also neutralized the anti‐apoptotic effect of resveratrol on N2a cells in the setting of cerebral IRI. Taken together our results show that mitochondrial damage is closely associated with the progression of cerebral IRI. In addition we also demonstrate the protective action played by resveratrol on reperfused brain and show that this effect is achieved via activating the AMPK‐Mfn1 pathway.

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Section: Discussionmentioning

confidence: 88%

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Gao

Wang

et al. 2019

Int J Experimental Path

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“…The prosurvival BCL-2 proteins, especially MCL-1 and BCL-X L , can sequester activated BAK, an inhibition process referred to as Mode 2 [27][28][29][60][61][62] (see Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…The unfolded activated BAK and BAX monomers can then dimerize via reciprocal BH3:groove interactions to form "symmetric homodimers" 12,13,[16][17][18][19][20][21][22] that cluster on the MOM to release apoptogenic factors from the mitochondrial intermembrane space [23][24][25] . Alternatively, the activated BAK and BAX monomers may bind to prosurvival members to form heterodimers that do not participate in pore formation [26][27][28][29][30] .…”

Section: Introductionmentioning

confidence: 99%

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

et al. 2020

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BAK and BAX, which drive commitment to apoptosis, are activated principally by certain BH3-only proteins that bind them and trigger major rearrangements. One crucial conformation change is exposure of their BH3 domain which allows BAK or BAX to form homodimers, and potentially to autoactivate other BAK and BAX molecules to ensure robust pore formation and cell death. Here, we test whether full-length BAK or mitochondrial BAX that are specifically activated by antibodies can then activate other BAK or BAX molecules. We found that antibody-activated BAK efficiently activated BAK as well as mitochondrial or cytosolic BAX, but antibody-activated BAX unexpectedly proved a poor activator. Notably, autoactivation by BAK involved transient interactions, as BAK and BAX molecules it activated could dissociate and homodimerize. The results suggest that BAK-driven autoactivation may play a substantial role in apoptosis, including recruitment of BAX to the mitochondria. Hence, directly targeting BAK rather than BAX may prove particularly effective in inhibiting unwanted apoptosis, or alternatively, inducing apoptosis in cancer cells.

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“…Several lines of evidence suggest that Bcl‐2 sequesters BH3 domain‐only molecules including Bad, Bim, and NOXA in stable mitochondrial complexes, inhibiting the activation of Bak and Bax . Furthermore, Hockings et al have reported that Mcl‐1 preferentially sequesters Bak in resistance to anticancer treatments, including BH3 mimetics. Our data showed that ascleposide significantly downregulated Bcl‐2 and Mcl‐1, while upregulated Bak protein expression, suggesting the contribution of the Bcl‐2 family members to mitochondrial damage.…”

Section: Discussionmentioning

confidence: 99%

Ascleposide, a natural cardenolide, induces anticancer signaling in human castration‐resistant prostatic cancer through Na⁺/K⁺‐ATPase internalization and tubulin acetylation

et al. 2020

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Background: Cardiac glycosides, which inhibit Na + /K + -ATPase, display inotropic effects for the treatment of congestive heart failure and cardiac arrhythmia. Recent studies have suggested signaling downstream of Na + /K + -ATPase action in the regulation of cell proliferation and apoptosis and have revealed the anticancer activity of cardiac glycosides. The study aims to characterize the anticancer potential of ascleposide, a natural cardenolide, and to uncover its primary target and underlying mechanism against human castration-resistant prostate cancer (CRPC).Methods: Cell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay, carboxyfluorescein succinimidyl ester staining assay and clonogenic examination. Flow cytometric analysis was used to detect the distribution of cell cycle phase, mitochondrial membrane potential, intracellular Na + and Ca 2+ levels, and reactive oxygen species production. Protein expression was examined using Western blot analysis. Endocytosis of Na + /K + -ATPase was determined using confocal immunofluorescence microscopic examination. Results: Ascleposide induced an increase of intracellular Na + and a potent antiproliferative effect. It also induced a decrease of G1 phase distribution while an increase in both G2/M and apoptotic sub-G1 phases, and downregulated several cell cycle regulator proteins, including cyclins, Cdk, p21, and p27 Cip/Kip proteins, Rb and c-Myc. Ascleposide decreased the expression of antiapoptotic Bcl-2 members (eg, Bcl-2 and Mcl-1) but upregulated proapoptotic member (eg, Bak), leading to a significant loss of mitochondrial membrane potential and activation of both caspase-9 and caspase-3. Ascleposide also dramatically induced tubulin acetylation, leading to inhibition of the catalytic activity of Na + /K + -ATPase. Notably, extracellular high K + (16 mM) significantly blunted ascleposide-mediated effects. Furthermore, ascleposide induced a p38 MAPK-dependent endocytosis of Na + /K + -ATPase and downregulated the protein expression of Na + /K + -ATPase α1 subunit. Wohn-Jenn Leu and Ching-Ting Wang equally contributed to this study. Conclusion: Ascleposide displays antiproliferative and apoptotic activities dependent on the inhibition of Na + /K + -ATPase pumping activity through p38 MAPK-mediated endocytosis of Na + /K + -ATPase and downregulation of α1 subunit, which in turn cause tubulin acetylation and cell cycle arrest. Cell apoptosis is ultimately triggered by the activation of caspase cascade attributed to mitochondrial damage through the downregulation of Bcl-2 and Mcl-1 protein expressions while upregulation of Bak protein levels. The data also suggest the potential of ascleposide in anti-CRPC development. K E Y W O R D S ascleposide, endocytosis, Na+/K+-ATPase α1-subunit, p38 MAPK, tubulin acetylation

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Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins

Cited by 51 publications

References 60 publications

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

Ascleposide, a natural cardenolide, induces anticancer signaling in human castration‐resistant prostatic cancer through Na⁺/K⁺‐ATPase internalization and tubulin acetylation

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Mcl-1 and Bcl-xL sequestration of Bak confers differential resistance to BH3-only proteins

Cited by 51 publications

References 60 publications

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important therapeutic target

Ascleposide, a natural cardenolide, induces anticancer signaling in human castration‐resistant prostatic cancer through Na+/K+‐ATPase internalization and tubulin acetylation

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Product

Resources

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Ascleposide, a natural cardenolide, induces anticancer signaling in human castration‐resistant prostatic cancer through Na⁺/K⁺‐ATPase internalization and tubulin acetylation