The Anaphase-Promoting Complex/Cyclosome Is a Cellular Ageing Regulator

Hu, Xiangdong; Jin, Xuejiao; Cao, Xiuling; Liu, Beidong

doi:10.3390/ijms232315327

Cited by 4 publications

(3 citation statements)

References 160 publications

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“…According to Hu et al. [ 45 ], the anaphase-promoting complex/cyclosome (APC/C) is a novel cellular aging regulator based on its indispensable role in the regulation of lifespan and its involvement in age-associated diseases of eukaryotic organisms. This consistency reinforces the results.…”

Section: Resultsmentioning

confidence: 99%

CellTICS: an explainable neural network for cell-type identification and interpretation based on single-cell RNA-seq data

Yin,

Chen

2023

Briefings in Bioinformatics

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Identifying cell types is crucial for understanding the functional units of an organism. Machine learning has shown promising performance in identifying cell types, but many existing methods lack biological significance due to poor interpretability. However, it is of the utmost importance to understand what makes cells share the same function and form a specific cell type, motivating us to propose a biologically interpretable method. CellTICS prioritizes marker genes with cell-type-specific expression, using a hierarchy of biological pathways for neural network construction, and applying a multi-predictive-layer strategy to predict cell and sub-cell types. CellTICS usually outperforms existing methods in prediction accuracy. Moreover, CellTICS can reveal pathways that define a cell type or a cell type under specific physiological conditions, such as disease or aging. The nonlinear nature of neural networks enables us to identify many novel pathways. Interestingly, some of the pathways identified by CellTICS exhibit differential expression “variability” rather than differential expression across cell types, indicating that expression stochasticity within a pathway could be an important feature characteristic of a cell type. Overall, CellTICS provides a biologically interpretable method for identifying and characterizing cell types, shedding light on the underlying pathways that define cellular heterogeneity and its role in organismal function. CellTICS is available at https://github.com/qyyin0516/CellTICS.

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Section: Resultsmentioning

confidence: 99%

CellTICS: an explainable neural network for cell-type identification and interpretation based on single-cell RNA-seq data

Yin,

Chen

2023

Briefings in Bioinformatics

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“…There is ample evidence supporting the idea that normal APC activity protects against cancer development. Many APC subunit mutations have been identified in a variety of spontaneous human cancers [19,21,51,52], which can cause cells to survive exposure to chemotherapy (acquired resistance); mutations in at least 7 different APC subunits have been associated with resistance to spindle assembly checkpoint inhibitors [11]. It has been observed that APC impairment is associated with an extended duration of mitosis, allowing time for increased DNA repair, for suppression of chromosome segregation errors, and avoidance of mitotic catastrophe [19], thus providing a rational mechanism whereby malignant cell populations survive cytotoxic chemotherapy exposures.…”

Section: Discussionmentioning

confidence: 99%

“…Another mechanism whereby impaired APC activity may contribute to cancer development, aggressive behavior, and treatment resistance may be due to the failure of pro-oncogenic APC substrates to be appropriately degraded, resulting in a cancer-promoting environment. Multiple APC substrates are known to contribute to cancer development and progression, and have repeatedly been found to be elevated in many cancers, presumably due to reduced APC function and blunting of its E3 activity to target and clear them via ubiquitin-dependent proteasomal degradation (see [20,51] and references therein). APC-targeted proteins, such as CDC20, Securin, HURP, FOXM1, PLK1, and the Aurora kinases, accumulate in multiple unrelated cancer types and are generally associated with more aggressive disease and worse clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Anaphase Promoting Complex Restores Impaired Mitotic Progression and Chemosensitivity in Multiple Drug Resistant Human Breast Cancer

Lubachowski,

VanGenderen,

Valentine

et al. 2024

Preprint

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The development of multiple drug resistant (MDR) cancer all too often signals the need for alternative toxic therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrated that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient derived xenograft (PDX) model of human breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemosensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, Doxorubicin (DOX). Using cell cycle arrest/release experiments we show that chemo-sensitive and -resistant MCF7 cells progress through the cell cycle at similar rates, but mitosis is delayed in MDR cells with elevated substrate levels. When treated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically-MDR human breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy.

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Activation of the Anaphase Promoting Complex Restores Impaired Mitotic Progression and Chemosensitivity in Multiple Drug-Resistant Human Breast Cancer

Lubachowski,

VanGenderen,

Valentine

et al. 2024

Cancers

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The development of multiple-drug-resistant (MDR) cancer all too often signals the need for alternative toxic therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrate that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug-sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type, or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient-derived xenograft (PDX) model of human triple-negative breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemo-sensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, doxorubicin (DOX). Using cell cycle arrest/release experiments, we show that mitosis is delayed in MDR cells with elevated substrate levels. When pretreated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically MDR human triple-negative breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy.

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The Anaphase-Promoting Complex/Cyclosome Is a Cellular Ageing Regulator

Cited by 4 publications

References 160 publications

CellTICS: an explainable neural network for cell-type identification and interpretation based on single-cell RNA-seq data

CellTICS: an explainable neural network for cell-type identification and interpretation based on single-cell RNA-seq data

Activation of the Anaphase Promoting Complex Restores Impaired Mitotic Progression and Chemosensitivity in Multiple Drug Resistant Human Breast Cancer

Activation of the Anaphase Promoting Complex Restores Impaired Mitotic Progression and Chemosensitivity in Multiple Drug-Resistant Human Breast Cancer

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