Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma

Xie, Jia; Xu, Xiuhua; Yin, Ping; Li, Yinuo; Guo, Haiyang; Kujawa, Stacy; Chakravarti, Debabrata; Bulun, Serdar E.; Kim, Julie; Wei, Jian‐Jun

doi:10.1038/s41374-018-0117-5

Cited by 18 publications

(20 citation statements)

References 32 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…4d). This suggests that MK2206 is capable of inducing cellular senescence being in line with Xie et al (2018) [26]. Surprisingly, by analyzing adherent cells, no reduction of SA-β-Gal positive cells by MK2206 after ENZ-induced cellular senescence was observed ( Fig.…”

Section: Ar Antagonist-induced Cellular Senescent Lncap Cells Are Sensupporting

confidence: 86%

See 1 more Smart Citation

Senolytic compounds control a distinct fate of androgen receptor agonist- and antagonist-induced cellular senescent LNCaP prostate cancer cells

et al. 2020

View full text Add to dashboard Cite

Background: The benefit of inducing cellular senescence as a tumor suppressive strategy remains questionable due to the senescence-associated secretory phenotype. Hence, studies and development of senolytic compounds that induce cell death in senescent cells have recently emerged. Senescent cells are hypothesized to exhibit different upregulated pro-survival/anti-apoptotic networks depending on the senescent inducers. This might limit the effect of a particular senolytic compound that targets rather only a specific pathway. Interestingly, cellular senescence in prostate cancer (PCa) cells can be induced by either androgen receptor (AR) agonists at supraphysiological androgen level (SAL) used in bipolar androgen therapy or by AR antagonists. This challenges to define ligand-specific senolytic compounds. Results: Here, we first induced cellular senescence by treating androgen-sensitive PCa LNCaP cells with either SAL or the AR antagonist Enzalutamide (ENZ). Subsequently, cells were incubated with the HSP90 inhibitor Ganetespib (GT), the Bcl-2 family inhibitor ABT263, or the Akt inhibitor MK2206 to analyze senolysis. GT and ABT263 are known senolytic compounds. We observed that GT exhibits senolytic activity specifically in SAL-pretreated PCa cells. Mechanistically, GT treatment results in reduction of AR, Akt, and phospho-S6 (p-S6) protein levels. Surprisingly, ABT263 lacks senolytic effect in both AR agonist-and antagonist-pretreated cells. ABT263 treatment does not affect AR, Akt, or S6 protein levels. Treatment with MK2206 does not reduce AR protein level and, as expected, potently inhibits Akt phosphorylation. However, ENZ-induced cellular senescent cells undergo apoptosis by MK2206, whereas SAL-treated cells are resistant. In line with this, we reveal that the pro-survival p-S6 level is higher in SAL-induced cellular senescent PCa cells compared to ENZ-treated cells. These data indicate a difference in the agonist-or antagonist-induced cellular senescence and suggest a novel role of MK2206 as a senolytic agent preferentially for AR antagonist-treated cells. Conclusion: Taken together, our data suggest that both AR agonist and antagonist induce cellular senescence but differentially upregulate a pro-survival signaling which preferentially sensitize androgen-sensitive PCa LNCaP cells to a specific senolytic compound.

show abstract

Section: Ar Antagonist-induced Cellular Senescent Lncap Cells Are Sensupporting

confidence: 86%

“…Both the HSP90 inhibitor GT and the Bcl-2 family inhibitor ABT263 have been described as senolytic agents [21][22][23]26]. Here, we show that both compounds inhibit LNCaP cell proliferation and induce apoptosis at higher concentrations (Additional file 1: Fig.…”

Section: Hsp90 Inhibitor Enhances Apoptosis Of Ar Agonist-induced Celmentioning

confidence: 70%

Senolytic compounds control a distinct fate of androgen receptor agonist- and antagonist-induced cellular senescent LNCaP prostate cancer cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…More importantly, elimination of radiation-induced senescent cells following thoracic radiation of mice ameliorated the accompanying pulmonary fibrosis [198]. Other reports have also demonstrated a potent senolytic activity of ABT263 against senescent osteoprogenitor cells, senescent human mesenchymal stromal cells, senescent cardiac myocytes, senescent pancreatic β-cells and uterine leiomyoma cells [199][200][201][202][203][204] (Table 2). Lastly, ABT263 has been proposed to be used sequentially as an adjunct to commonly used senescence-inducing anticancer therapy, such as topoisomerase and aurora kinase inhibitors, as a novel therapeutic approach for cancer treatment [145].…”

Section: Navitoclax (Abt263)mentioning

confidence: 89%

“…Dasatinib + Quercetin -Senescent HUVEC, senescent preadipocytes in vitro -Senescent MEFs, senescent bone marrow-derived murine mesenchymal stem cells in vivo -SA-β-gal positive muscle and fat tissue of irradiated single mouse limb -Progeroid Ercc1(−/∆) mice [186] -Senescent lung fibroblasts and epithelial cells in bleomycin-induced lung injury/idiopathic pulmonary fibrosis mouse model [18] -Senescent alveolar epithelial type (AT)II ex vivo in bleomycin-induced lung injury/idiopathic pulmonary fibrosis mouse model. [187] -Senescent medial aortal cells of aging mice and hypercholesterolemia (atherosclerosis) mouse models [188] -Senescent hepatocytes of dietary hepatic steatosis mouse model [189] -Radiation-induced senescent preadipocytes in vivo -Senescent cells in freshly isolated human omental adipose tissue of obese individuals ex vivo [190] -Arteriovenous fistula-chronic kidney disease mouse model [191] -20-month-old, transgenic tau NFT -Mapt 0/0 mice [192] -Aβ plaque-associated senescent oligodendrocyte progenitor cells in vivo -ZsGreen/APPPS1 p16 INK4 reporter Alzheimer's disease mouse model -Radiation-induced senescent N2a cells [193] -Uterine fibrosis mouse model [194] -Telomere dysfunction-induced senescent osteoblasts and osteocytes [195] Navitoclax (ABT263) -Radiation-induced, replication-exhausted and Ras-induced senescent WI38 fibroblasts in vitro -Radiation-induced senescent human IMR90 fibroblasts, human renal epithelial cells and mouse embryonic fibroblasts in vitro -Radiation-induced senescence in p16-3MR transgenic mouse model [196] -Radiation-induced senescent human umbilical vein epithelial cells, IMR90 human lung fibroblasts and mouse embryonic fibroblasts [197] -Radiation-induced senescent type II alveolar epithelial cells in vitro and in vivo [198] -Senescent pancreatic tissue of i4F mouse model [199] -Replicative-exhausted human mesenchymal stromal cells [200] -Aging-induced senescent cardiac myocytes -Myocardial infarction mouse model [201] -Senescent murine pancreatic β-cells in vitro and in vivo [202] -Aging mouse bone marrow stromal cells [203] -WIPI1 and SLITKR4 overexpression-induced senescent uterine leiomyoma spheroid model ex vivo [204]…”

Section: Senolytic Model/cell Line Referencementioning

confidence: 99%

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

197

150

View full text Add to dashboard Cite

For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

show abstract

“…Organoids have also been used to model age-associated diseases. For instance, 3D cultures have been developed to study osteoarthritis [ 53 ], macular degeneration [ 54 ], uterine leiomyoma [ 55 ], or Alzheimer’s disease [ 56 ], which will be discussed in the next section. Before organoids can become important aging models, some issues must be considered such as the lower efficiency found when reprogramming cells to form organoids from aged donors compared to young ones or the increase in senescence rate when cultured for long time [ 57 , 58 , 59 ].…”

Section: Organoids As a Model To Study Aging Signature Across Tissuesmentioning

confidence: 99%

Organoids: An Emerging Tool to Study Aging Signature across Human Tissues. Modeling Aging with Patient-Derived Organoids

Torrens‐Mas

Perelló-Reus

Navas-Enamorado

et al. 2021

IJMS

View full text Add to dashboard Cite

The biology of aging is focused on the identification of novel pathways that regulate the underlying processes of aging to develop interventions aimed at delaying the onset and progression of chronic diseases to extend lifespan. However, the research on the aging field has been conducted mainly in animal models, yeast, Caenorhabditis elegans, and cell cultures. Thus, it is unclear to what extent this knowledge is transferable to humans since they might not reflect the complexity of aging in people. An organoid culture is an in vitro 3D cell-culture technology that reproduces the physiological and cellular composition of the tissues and/or organs. This technology is being used in the cancer field to predict the response of a patient-derived tumor to a certain drug or treatment serving as patient stratification and drug-guidance approaches. Modeling aging with patient-derived organoids has a tremendous potential as a preclinical model tool to discover new biomarkers of aging, to predict adverse outcomes during aging, and to design personalized approaches for the prevention and treatment of aging-related diseases and geriatric syndromes. This could represent a novel approach to study chronological and/or biological aging, paving the way to personalized interventions targeting the biology of aging.

show abstract

Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma

Cited by 18 publications

References 32 publications

Senolytic compounds control a distinct fate of androgen receptor agonist- and antagonist-induced cellular senescent LNCaP prostate cancer cells

Senolytic compounds control a distinct fate of androgen receptor agonist- and antagonist-induced cellular senescent LNCaP prostate cancer cells

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Organoids: An Emerging Tool to Study Aging Signature across Human Tissues. Modeling Aging with Patient-Derived Organoids

Contact Info

Product

Resources

About