Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice

Cottage, Christopher T.; Peterson, Norman C.; Kearley, Jennifer; Berlin, Aaron A.; Xiong, Ximing; Huntley, Anna; Zhao, Weiguang; Brown, Charles O.; Migneault, Annik; Zerrouki, Kamelia; Criner, G.J.; Kolbeck, Roland; Connor, Jane R.; Lemaire, Raphaël

doi:10.1038/s42003-019-0532-1

Cited by 46 publications

(44 citation statements)

References 57 publications

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“…Many studies have reported that p53/p21 pathway activation is responsible for inducing cellular senescence (58)(59)(60). Furthermore, the activation of p16/pRb signaling is a vital indicator of senescence (58,61). This study demonstrated that paclitaxel suppressed the expression of p53, p21, hypophosphorylated pRb and p16, which might be linked to the elimination of cellular senescence of PC9-MET cells (Figure 7).…”

Section: Discussionmentioning

confidence: 55%

The Mechanisms of the Growth Inhibitory Effects of Paclitaxel on Gefitinib-resistant Non-small Cell Lung Cancer Cells

Mohiuddin

Kondo

2021

Cancer Genomics Proteomics

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Background/Aim: Coronavirus disease 2019 (COVID-19) poses a great challenge for the treatment of cancer patients. It presents as a severe respiratory infection in aged individuals, including some lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. In addition, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence, can worsen COVID-19. Given this situation, we investigated the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant non-small-cell lung cancer (NSCLC) cells (PC9-MET) to clarify the underlying mechanisms. Materials and Methods: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, a reactive oxygen species (ROS) assay, SA-β-Gal staining, a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Western blotting. Results: Paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3 (Asp 175), cleaved caspase-9 (Asp 330) and cleaved PARP (Asp 214). In addition, paclitaxel increased ROS production, leading to DNA damage. Inhibition of ROS production by N-acetylcysteine attenuates paclitaxel-induced DNA damage. Importantly, paclitaxel eliminated cellular senescence, as observed by SAβ-Gal staining. Cellular senescence elimination was associated with p53/p21 and p16/pRb signaling inactivation. Conclusion: Paclitaxel may be a promising anticancer drug and offer a new therapeutic strategy for managing gefitinib-resistant NSCLC during the COVID-19 pandemic.

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Section: Discussionmentioning

confidence: 55%

The Mechanisms of the Growth Inhibitory Effects of Paclitaxel on Gefitinib-resistant Non-small Cell Lung Cancer Cells

Mohiuddin

Kondo

2021

Cancer Genomics Proteomics

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“…Employing Pathway Studio-guided "Shortest Path analysis" allowed us to explore plausible connections between these two genes and COPD, simultaneously highlighting a set of common interactors, which includes the signaling molecule and the pro-inflammatory cytokines. Among these, a connection of both TNFRSF12A and CD38 proteins to AKT1 is remarkable, as the stimulation of IGF1/AKT1 axis via the targeting of p16-induced senescence was recently shown to alleviate at least some phenotypic features of COPD (Cottage et al, 2019). Notably, among other connecting molecules are proinflammatory cytokines TNF-α, IL-1β, IFN-γ, and IL-6, which are the part of the SASP phenotype (Barnes, 2014;Ohtani, 2019).…”

Section: Discussionmentioning

confidence: 99%

TNFRSF12A and CD38 Contribute to a Vicious Circle for Chronic Obstructive Pulmonary Disease by Engaging Senescence Pathways

Dong

Cao

et al. 2020

Front. Cell Dev. Biol.

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Pathogenesis of chronic obstructive pulmonary disease (COPD) is dependent on chronic inflammation and is hypothesized to represent organ-specific senescence phenotype. Identification of senescence-associated gene drivers for the development of COPD is warranted. By employing automated pipeline, we have compiled lists of the genes implicated in COPD (N = 918) and of the genes changing their activity along with cell senescence (N = 262), with a significant (p < 7.06e −60 ) overlap between these datasets (N = 89). A mega-analysis and a partial mega-analysis were conducted for gene sets linked to senescence but not yet to COPD, in nine independent mRNA expression datasets comprised of tissue samples of COPD cases (N = 171) and controls (N = 256). Mega-analysis of expression has identified CD38 and TNFRSF12A (p < 2.12e −8 ) as genes not yet explored in a context of senescence-COPD connection. Functional pathway enrichment analysis allowed to generate a model, which explains accelerated aging phenotypes previously observed in COPD patients. Presented results call for investigation of the role of TNFRSF12A/CD38 balance in establishing a vicious cycle of unresolvable tissue remodeling in COPD lungs.

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“…Furthermore, impaired immune responses characterised by reduced clearance capacity and higher susceptibility to infections are related to the accumulation of senescent T-lymphocytes and macrophages in COPD lungs [64]. Although studies depleting senescent cells using genetic models have generated conflicting results [79][80][81], the pharmacological depletion of senescent cells using the senolytic drug ABT-263 conferred resistance to elastase-induced emphysema in both young and aged mice [79].…”

Section: Regeneration Of a Diseased Lung Chronic Diseasesmentioning

confidence: 99%

Lung regeneration: implications of the diseased niche and ageing

et al. 2020

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Most chronic and acute lung diseases have no cure, leaving lung transplantation as the only option. Recent work has improved our understanding of the endogenous regenerative capacity of the lung and has helped identification of different progenitor cell populations, as well as exploration into inducing endogenous regeneration through pharmaceutical or biological therapies. Additionally, alternative approaches that aim at replacing lung progenitor cells and their progeny through cell therapy, or whole lung tissue through bioengineering approaches, have gained increasing attention. Although impressive progress has been made, efforts at regenerating functional lung tissue are still ineffective. Chronic and acute lung diseases are most prevalent in the elderly and alterations in progenitor cells with ageing, along with an increased inflammatory milieu, present major roadblocks for regeneration. Multiple cellular mechanisms, such as cellular senescence and mitochondrial dysfunction, are aberrantly regulated in the aged and diseased lung, which impairs regeneration. Existing as well as new human in vitro models are being developed, improved and adapted in order to study potential mechanisms of lung regeneration in different contexts. This review summarises recent advances in understanding endogenous as well as exogenous regeneration and the development of in vitro models for studying regenerative mechanisms.

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Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice

Cited by 46 publications

References 57 publications

The Mechanisms of the Growth Inhibitory Effects of Paclitaxel on Gefitinib-resistant Non-small Cell Lung Cancer Cells

The Mechanisms of the Growth Inhibitory Effects of Paclitaxel on Gefitinib-resistant Non-small Cell Lung Cancer Cells

TNFRSF12A and CD38 Contribute to a Vicious Circle for Chronic Obstructive Pulmonary Disease by Engaging Senescence Pathways

Lung regeneration: implications of the diseased niche and ageing

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