BAX-BAK1-independent LC3B lipidation by BH3 mimetics is unrelated to BH3 mimetic activity and has only minimal effects on autophagic flux

Reljić, Boris; Conos, Stephanie A.; Lee, Erinna F.; Garnier, Jean‐Marc; Li, Dong; Lessène, Guillaume; Fairlie, W. Douglas; Vaux, David L.; Lindqvist, Lisa

doi:10.1080/15548627.2016.1179406

Cited by 18 publications

(17 citation statements)

References 36 publications

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“…This result was consistent with other studies [18,22]. However, newly evidences showed ABT-263 induced autophagy in a BAX-and BAK1-dependent manner [23]. Thus, further studies are needed to elucidate the more detailed mechanism of this compound on inducing autophagy.…”

Section: Discussionsupporting

confidence: 91%

Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

Tang¹,

Lu²,

Xu³

et al. 2020

Preprint

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Sepsis is a critical challenge for the elderly population as the immune function is less responsive by aging. Although cell numbers seem preserved in the elderly, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. an inhibitor of the anti-apoptotic protein Bcl2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues. Therefore, we treated the aged mouse with ABT-263 and used cecal slurry injection to induce sepsis to observe its effect on the survival rate of sepsis. Besides, we isolated peritoneal macrophages from the aged mouse to investigate the cell function and molecular mechanism. 3-methyladenine (3-MA), a phosphatidylinositol 3-kinases (PI3K) inhibitor, and rapamycin, an autophagy-enhancer, were used to block or mimic the autophagy, respectively. EGFP-expressing E. Coli was used as a marker to evaluate the phagocytic ability of macrophages. The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy. Additionally, It is revealed that ABT-263 induced autophagy and enhanced the phagocytic ability of the peritoneal macrophages. However, blocking the autophagy can eliminate this effect. In conclusion, ABT-263 enhanced the macrophage function by inducing autophagy, consequently, protected the aged mouse from sepsis. YZ took the lead in drafting this manuscript. YZ and LHT carried out the experiments and acquired the raw data. JL and LMX analysed and interpretation the data. BLC provided critical feedback and consultation. JYX conceived and planned the experiments. All authors read and approved the final manuscript.

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Section: Discussionsupporting

confidence: 91%

Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

Tang¹,

Lu²,

Xu³

et al. 2020

Preprint

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“…107,[111][112][113] Although several laboratories have provided evidence supporting the connection between Beclin-1 and BCL-2 family members, recent studies have challenged this model, proposing an alternative mechanism whereby prosurvival BCL-2 proteins inhibit autophagy only indirectly, through their interaction with and sequestration of proapoptotic BAX and BAK. 114,115 However, another study indicated that BAX and BAK are dispensable for ABT-737-induced autophagy. 116 Further studies are necessary to precisely determine the functional interplay between the BCL-2 family and components of the autophagy machinery.…”

Section: Stress Signal Integration At the Er Membrane By The Bcl-2 Famentioning

confidence: 99%

BCL-2 family: integrating stress responses at the ER to control cell demise

2017

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In the last decade, the endoplasmic reticulum (ER) has emerged as a central organelle regulating the core mitochondrial apoptosis pathway. At the ER membrane, a variety of stress signals are integrated toward determining cell fate, involving a complex cross talk between key homeostatic pathways including the unfolded protein response, autophagy, calcium signaling and mitochondrial bioenergetics. In this context, key regulators of cell death of the BCL-2 and TMBIM/BI-1 family of proteins have relevant functions as stress rheostats mediated by the formation of distinct protein complexes that regulate the switch between adaptive and proapoptotic phases under stress. Here, we overview recent advances on our molecular understanding of how the apoptotic machinery integrates stress signals toward cell fate decisions upstream of the mitochondrial gateway of death.

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“…Multiple studies have demonstrated that BH3 mimetics modify autophagic activity in a variety of cancer cell types [22] . Therefore, we studied the effect of ABT-263 on autophagy by measuring LC3-II and p62 protein expression.…”

Section: Abt-263 Promoted Pro-survival Autophagymentioning

confidence: 99%

ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro

Lin

Que

et al. 2017

Acta Pharmacol Sin

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Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC values of 10.7±1.4, 7.1±1.5 and 8.2±1.6 μmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5-20 μmol/L) dose-dependently induced G/G-phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G/G-phase arrest. Knockdown of p21 attenuated ABT-263-induced G/G-phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity.

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BAX-BAK1-independent LC3B lipidation by BH3 mimetics is unrelated to BH3 mimetic activity and has only minimal effects on autophagic flux

Cited by 18 publications

References 36 publications

Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

BCL-2 family: integrating stress responses at the ER to control cell demise

ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro

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