A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells

Wakita, Masahiro; Takahashi, Akiko; Sano, Osamu; Loo, Tze Mun; Imai, Yoshinori; Narukawa, Megumi; Iwata, Hidehisa; Matsudaira, Tatsuyuki; Kawamoto, Shimpei; Ohtani, Naoko; Yoshimori, Tamotsu; Hara, Eiji

doi:10.1038/s41467-020-15719-6

Cited by 146 publications

(129 citation statements)

References 52 publications

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“…It will be interesting to see what results come from the recently initiated phase I study to evaluate safety, tolerability, and the pharmacokinetics of intravitreal delivered administration of UBX1325 in patients diagnosed with diabetic macular edema [ 65 , 171 ]. Additionally, synthesized small compounds targeting other pro-survival pathways, such as inhibitors of bromo and extraterminal domain (BET) proteins, have been identified via high-throughput screening and show promising therapeutic value as they attenuated RPE cell loss in vitro and protected ganglion cells in vivo [ 172 , 173 ].…”

Section: Antagonizing Senescence In the Eye Opens A Therapeutic Windomentioning

confidence: 99%

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Lee

Lin

Copland

et al. 2021

J Neuroinflammation

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Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

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Section: Antagonizing Senescence In the Eye Opens A Therapeutic Windomentioning

confidence: 99%

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Lee

Lin

Copland

et al. 2021

J Neuroinflammation

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“…Altogether, we have elucidated that DNA damage can provoke senescence-associated EV (SA-EV) secretion by activating the ceramide pathway, thereby helping to eliminate hazardous DNA fragments from cells. It is notable that there might be alternative mechanisms for SA-EV secretion, and these could be potential therapeutic targets for the prevention of SASP, along with senolytic drugs to eliminate senescent cells [67]. Therefore, we will conduct further studies to address the molecular mechanisms underlying SA-EV biogenesis.…”

Section: Discussionmentioning

confidence: 99%

DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses

Hitomi

Okada

Loo

et al. 2020

IJMS

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DNA damage, caused by various oncogenic stresses, can induce cell death or cellular senescence as an important tumor suppressor mechanism. Senescent cells display the features of a senescence-associated secretory phenotype (SASP), secreting inflammatory proteins into surrounding tissues, and contributing to various age-related pathologies. In addition to this inflammatory protein secretion, the release of extracellular vesicles (EVs) is also upregulated in senescent cells. However, the molecular mechanism underlying this phenomenon remains unclear. Here, we show that DNA damage activates the ceramide synthetic pathway, via the downregulation of sphingomyelin synthase 2 (SMS2) and the upregulation of neutral sphingomyelinase 2 (nSMase2), leading to an increase in senescence-associated EV (SA-EV) biogenesis. The EV biogenesis pathway, together with the autophagy-mediated degradation pathway, functions to block apoptosis by removing cytoplasmic DNA fragments derived from chromosomal DNA or bacterial infections. Our data suggest that this SA-EV pathway may play a prominent role in cellular homeostasis, particularly in senescent cells. In summary, DNA damage provokes SA-EV release by activating the ceramide pathway to protect cells from excessive inflammatory responses.

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“…Another example is the bromodomain and extra-terminal domain (BET) family protein degrader (BETd) which was identified as a senolytic by high-throughput screening. BETd therapy removes senescent HSCs in adipose mouse liver, thereby inhibiting the progression of liver cancer [182]. Since HCC formation is often associated with SASP release in senescent HSCs, inhibition of SASP release or the reduction of their disease-causing phenotypes as a therapeutic target might be an appropriate approach.…”

Section: Functional Role Of Senescence In Light Of the Development Ofmentioning

confidence: 99%

Molecular Mechanisms to Target Cellular Senescence in Hepatocellular Carcinoma

Mittermeier

Konopa

Muehlich

2020

Cells

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Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death and is the most common type of liver cancer. Due to the current paucity of drugs for HCC therapy there is a pressing need to develop new therapeutic concepts. In recent years, the role of Serum Response Factor (SRF) and its coactivators, Myocardin-Related Transcription Factors A and B (MRTF-A and -B), in HCC formation and progression has received considerable attention. Targeting MRTFs results in HCC growth arrest provoked by oncogene-induced senescence. The induction of senescence acts as a tumor-suppressive mechanism and therefore gains consideration for pharmacological interventions in cancer therapy. In this article, we describe the key features and the functional role of senescence in light of the development of novel drug targets for HCC therapy with a focus on MRTFs.

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A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells

Cited by 146 publications

References 52 publications

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses

Molecular Mechanisms to Target Cellular Senescence in Hepatocellular Carcinoma

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