ROS-induced cell cycle arrest as a mechanism of resistance in polyaneuploid cancer cells (PACCs)

Kuczler, Morgan D.; Olseen, Athen M.; Pienta, Kenneth J.; Amend, Sarah R.

doi:10.1016/j.pbiomolbio.2021.05.002

Cited by 45 publications

(26 citation statements)

References 47 publications

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“…It is known that ROS are the mechanism of Ang II-induced VSMC senescence [ 1 , 20 , 21 ], and ROS induces cell cycle arrest [ 22 ]. Therefore, we confirmed the influence of ANXA6 on Ang II-induced ROS.…”

Section: Resultsmentioning

confidence: 99%

EZH2 Regulates ANXA6 Expression via H3K27me3 and Is Involved in Angiotensin II-Induced Vascular Smooth Muscle Cell Senescence

Guo

Zhao

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objectives. Abdominal aortic aneurysm (AAA) has a high risk of rupture of the aorta and is one of the leading causes of death in older adults. This study is aimed at confirming the influence and mechanism of the abnormally expressed ANXA6 gene in AAA. Methods. Clinical samples were collected for proteome sequencing to screen for differentially expressed proteins. An Ang II-induced vascular smooth muscle cell (VSMC) aging model as well as an AAA animal model was used. Using RT-qPCR to detect the mRNA levels of EZH2, ANXA6, IK-6, and IL-8 in cells and tissues were assessed. Western blotting and immunohistochemistry staining were used apply for the expression of associated proteins in cells and tissues. SA-β-gal staining, flow cytometry, and DHE staining were used to detect senescent cells and the level of ROS. The cell cycle was assessed by flow cytometry. Arterial pathology was observed by HE staining. The aging of VSMCs in arterial tissue was assessed by coimmunofluorescence for α-SMA and p53. Results. There were 24 differentially expressed proteins in the AAA clinical samples, including 10 upregulated protein and 14 downregulated protein, and the differential expression of ANXA6 was associated with vascular disease. Our study found that ANXA6 was highly expressed and EZH2 was lowly expressed in an Ang II-induced VSMC aging model. Knockdown of ANXA6 or overexpression of EZH2 inhibited Ang II-induced ROS, inhibited cell senescence, decreased Ang II evoked G1 arrest, and increased cells in G2 phase, while overexpression of ANXA6 played the opposite role. Overexpression of EZH2 inhibited ANXA6 expression by increasing H3K27me3 modification at the ANXA6 promoter. Simultaneous overexpression of EZH2 and the protective effect of EZH2 on cell senescence were partially reversed by ANXA6. Similarly, ANXA6 was highly expressed and EZH2 was lowly expressed in an Ang II-induced AAA animal model. Knockdown of ANXA6 and overexpression of EZH2 alleviated Ang II-induced VSMC senescence and inhibited AAA progression, while simultaneous overexpression of EZH2 and ANXA6 partially reversed the protective effect of EZH2 on AAA. Conclusion. EZH2 regulates the ANXA6 promoter H3K27me3 modification, inhibits ANXA6 expression, alleviates Ang II-induced VSMC senescence, and inhibits AAA progression.

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Section: Resultsmentioning

confidence: 99%

EZH2 Regulates ANXA6 Expression via H3K27me3 and Is Involved in Angiotensin II-Induced Vascular Smooth Muscle Cell Senescence

Guo

Zhao

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Overwhelming oxidative stress production is a promising treatment against cancer cells, accompanied by cell cycle arrest [ 48 ], apoptosis [ 49 ], caspase activation [ 50 ], and DNA damage [ 51 ]. Oxidative stress may trigger a DNA damage response.…”

Section: Discussionmentioning

confidence: 99%

“…When DNA damage is too severe, cell cycle progression is prone to be arrested for cell cycle checkpoint examination. Once the DNA damage exceeds the tolerance, cells may process apoptosis [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Methanol Extract of Clavularia inflata Exerts Apoptosis and DNA Damage to Oral Cancer Cells

et al. 2022

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Antiproliferation effects of Clavularia-derived natural products against cancer cells have been reported on, but most studies have focused on identifying bioactive compounds, lacking a detailed investigation of the molecular mechanism. Crude extracts generally exhibit multiple targeting potentials for anticancer effects, but they have rarely been assessed for methanol extracts of Clavularia inflata (MECI). This investigation aims to evaluate the antiproliferation of MECI and to examine several potential mechanisms between oral cancer and normal cells. A 24 h MTS assay demonstrated that MECI decreased cell viability in several oral cancer cell lines more than in normal cells. N-acetylcysteine (NAC), an oxidative stress inhibitor, recovered these antiproliferation effects. Higher oxidative stress was stimulated by MECI in oral cancer cells than in normal cells, as proven by examining reactive oxygen species and mitochondrial superoxide. This preferential induction of oxidative stress was partly explained by downregulating more cellular antioxidants, such as glutathione, in oral cancer cells than in normal cells. Consequently, the MECI-generated high oxidative stress in oral cancer cells was preferred to trigger more subG1 population, apoptosis expression (annexin V and caspase activation), and DNA damage, reverted by NAC. In conclusion, MECI is a potent marine natural product showing preferential antiproliferation against oral cancer cells.

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“…PACCs are formed when aneuploid cancer cells bypass mitosis, cytokinesis, or both and undergo whole genome doubling via cell fusion, endocycling, or mitotic slippage. This cell state is characterized by (1) an exit of the cell cycle after S phase to pause cell division 21 , allowing PACCs to endure stressful environments by avoiding DNA damage and programmed cell death, and (2) an increase in genomic content through polyploidization, promoting a greater generation of heritable variation that can be dispensed to their aneuploid 2N+ progeny upon depolyploidization via neosis or multipolar cell division 22 – 25 . This leads to the rapid generation of heritably resistant cells.…”

Section: Introductionmentioning

confidence: 99%

A life history model of the ecological and evolutionary dynamics of polyaneuploid cancer cells

Bukkuri

Pienta²,

Austin

et al. 2022

Sci Rep

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Therapeutic resistance is one of the main reasons for treatment failure in cancer patients. The polyaneuploid cancer cell (PACC) state has been shown to promote resistance by providing a refuge for cancer cells from the effects of therapy and by helping them adapt to a variety of environmental stressors. This state is the result of aneuploid cancer cells undergoing whole genome doubling and skipping mitosis, cytokinesis, or both. In this paper, we create a novel mathematical framework for modeling the eco-evolutionary dynamics of state-structured populations and use this framework to construct a model of cancer populations with an aneuploid and a PACC state. Using in silico simulations, we explore how the PACC state allows cancer cells to (1) survive extreme environmental conditions by exiting the cell cycle after S phase and protecting genomic material and (2) aid in adaptation to environmental stressors by increasing the cancer cell’s ability to generate heritable variation (evolvability) through the increase in genomic content that accompanies polyploidization. In doing so, we demonstrate the ability of the PACC state to allow cancer cells to persist under therapy and evolve therapeutic resistance. By eliminating cells in the PACC state through appropriately-timed PACC-targeted therapies, we show how we can prevent the emergence of resistance and promote cancer eradication.

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ROS-induced cell cycle arrest as a mechanism of resistance in polyaneuploid cancer cells (PACCs)

Cited by 45 publications

References 47 publications

EZH2 Regulates ANXA6 Expression via H3K27me3 and Is Involved in Angiotensin II-Induced Vascular Smooth Muscle Cell Senescence

EZH2 Regulates ANXA6 Expression via H3K27me3 and Is Involved in Angiotensin II-Induced Vascular Smooth Muscle Cell Senescence

Methanol Extract of Clavularia inflata Exerts Apoptosis and DNA Damage to Oral Cancer Cells

A life history model of the ecological and evolutionary dynamics of polyaneuploid cancer cells

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