The proteostasis burden of aneuploidy

Amponsah, Prince Saforo; Štorchová, Zuzana

doi:10.1515/hsz-2024-0163

Biological Chemistry

2025

DOI: 10.1515/hsz-2024-0163

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The proteostasis burden of aneuploidy

Prince Saforo Amponsah¹,

Zuzana Štorchová²

Abstract: Aneuploidy refers to chromosome number abnormality that is not an exact multiple of the haploid chromosome set. Aneuploidy has largely negative consequences in cells and organisms, manifested as so-called aneuploidy-associated stresses. A major consequence of aneuploidy is proteotoxic stress due to abnormal protein expression from imbalanced chromosome numbers. Recent advances have improved our understanding of the nature of the proteostasis imbalance caused by aneuploidy and highlighted their relevance with r… Show more

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Cited by 2 publications

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“…One major consequence of cells becoming aneuploid is the resultant proteotoxic stress [ 2 , 5 ] ( Figure 1 ). This stress is thought to be derived from three primary sources: First, aneuploidy leads to measured stoichiometric imbalances in the expression levels of the protein components of multi-protein complexes, causing essential protein chaperones, such as heat-shock protein 90 (HSP90), to become limiting for viability in cells [ 2 , 5 , 6 ]. This limitation likely emerges from a loss of buffering capacity, namely, an ability to tolerate a natural load on the protein-folding machinery in the cell.…”

Section: Cancer Cell Proteotoxic Stress and Aneuploidymentioning

confidence: 99%

“…Buffering capacity is a fundamental cell biological function necessary for cell viability and is a core requisite function to achieve proper cellular proteostasis. Cancer cells are likely to become more dependent on these buffering capacity systems as they develop aneuploidy, which is a weakness that may have the potential to be exploited therapeutically [ 2 , 5 , 6 ].…”

Section: Cancer Cell Proteotoxic Stress and Aneuploidymentioning

confidence: 99%

“…Exploiting proteotoxic stress directly, by targeting the mechanisms that help cells respond to and recover from such stress, has long been the target of anti-cancer therapeutics [ 2 , 3 , 11 , 12 ]. This has resulted in several anti-cancer successes including Food and Drug Administration (FDA)-approved 26S proteosome inhibitors such as bortezomib, carfilzomib, and ixazomib; the Histone Deacetylase 6 (HDAC6) inhibitor panobinostat; and pimitespib (TAS-116), an HSP90 inhibitor approved for use against stomach cancer in Japan [ 3 ].…”

Section: Cancer Cell Proteotoxic Stress and Aneuploidymentioning

confidence: 99%

“… The agent should avoid the induction of the Senescence-Associated Secretory Phenotype (SASP) response in tumor cells which is known to be a contributing factor in promoting further aggressive malignancies after the completion of a round of, for example, chemotherapy [ 31 ]. Here, we have a higher concern that any agent that aggravates proteotoxic stress may elevate the SASP response because it is known that one pathway cells use to suppress proteotoxic stress is to secrete portions of the cytoplasm as exosomes [ 2 ]. The agent cannot induce the overexpression of programmed cell death-ligand 1 (PD-L1) on the surface of the target cancer cells as this will likely contribute to the suppression of immunogenic cell death that is promoted by the cGAS-STING/type I interferon secretion pathway.…”

Section: Targeting the Apc/c To Suppress Cell Division Cycle Progress...mentioning

confidence: 99%

“…The agent should avoid the induction of the Senescence-Associated Secretory Phenotype (SASP) response in tumor cells which is known to be a contributing factor in promoting further aggressive malignancies after the completion of a round of, for example, chemotherapy [ 31 ]. Here, we have a higher concern that any agent that aggravates proteotoxic stress may elevate the SASP response because it is known that one pathway cells use to suppress proteotoxic stress is to secrete portions of the cytoplasm as exosomes [ 2 ].…”

Section: Targeting the Apc/c To Suppress Cell Division Cycle Progress...mentioning

confidence: 99%

See 4 more Smart Citations

Tick-Tock: Cancer Cell Division Cycle Clocks Strike Midnight

Schuyler

¹

,

Chen

²

,

Nguyen

³

et al. 2025

IJMS

0

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Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

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“…One major consequence of cells becoming aneuploid is the resultant proteotoxic stress [ 2 , 5 ] ( Figure 1 ). This stress is thought to be derived from three primary sources: First, aneuploidy leads to measured stoichiometric imbalances in the expression levels of the protein components of multi-protein complexes, causing essential protein chaperones, such as heat-shock protein 90 (HSP90), to become limiting for viability in cells [ 2 , 5 , 6 ]. This limitation likely emerges from a loss of buffering capacity, namely, an ability to tolerate a natural load on the protein-folding machinery in the cell.…”

Section: Cancer Cell Proteotoxic Stress and Aneuploidymentioning

confidence: 99%

“…Buffering capacity is a fundamental cell biological function necessary for cell viability and is a core requisite function to achieve proper cellular proteostasis. Cancer cells are likely to become more dependent on these buffering capacity systems as they develop aneuploidy, which is a weakness that may have the potential to be exploited therapeutically [ 2 , 5 , 6 ].…”

Section: Cancer Cell Proteotoxic Stress and Aneuploidymentioning

confidence: 99%

“…Exploiting proteotoxic stress directly, by targeting the mechanisms that help cells respond to and recover from such stress, has long been the target of anti-cancer therapeutics [ 2 , 3 , 11 , 12 ]. This has resulted in several anti-cancer successes including Food and Drug Administration (FDA)-approved 26S proteosome inhibitors such as bortezomib, carfilzomib, and ixazomib; the Histone Deacetylase 6 (HDAC6) inhibitor panobinostat; and pimitespib (TAS-116), an HSP90 inhibitor approved for use against stomach cancer in Japan [ 3 ].…”

Section: Cancer Cell Proteotoxic Stress and Aneuploidymentioning

confidence: 99%

“… The agent should avoid the induction of the Senescence-Associated Secretory Phenotype (SASP) response in tumor cells which is known to be a contributing factor in promoting further aggressive malignancies after the completion of a round of, for example, chemotherapy [ 31 ]. Here, we have a higher concern that any agent that aggravates proteotoxic stress may elevate the SASP response because it is known that one pathway cells use to suppress proteotoxic stress is to secrete portions of the cytoplasm as exosomes [ 2 ]. The agent cannot induce the overexpression of programmed cell death-ligand 1 (PD-L1) on the surface of the target cancer cells as this will likely contribute to the suppression of immunogenic cell death that is promoted by the cGAS-STING/type I interferon secretion pathway.…”

Section: Targeting the Apc/c To Suppress Cell Division Cycle Progress...mentioning

confidence: 99%

“…The agent should avoid the induction of the Senescence-Associated Secretory Phenotype (SASP) response in tumor cells which is known to be a contributing factor in promoting further aggressive malignancies after the completion of a round of, for example, chemotherapy [ 31 ]. Here, we have a higher concern that any agent that aggravates proteotoxic stress may elevate the SASP response because it is known that one pathway cells use to suppress proteotoxic stress is to secrete portions of the cytoplasm as exosomes [ 2 ].…”

Section: Targeting the Apc/c To Suppress Cell Division Cycle Progress...mentioning

confidence: 99%

See 3 more Smart Citations

Tick-Tock: Cancer Cell Division Cycle Clocks Strike Midnight

Schuyler

¹

,

Chen

²

,

Nguyen

³

et al. 2025

IJMS

0

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

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