Everolimus Triggers Cytokine Release by Macrophages

Martinet, Wim; Verheye, Stefan; Meyer, Inge De; Timmermans, Jean‐Pierre; Schrijvers, Dorien M.; Brussel, Ilse Van; Bult, Hidde; Meyer, Guido

doi:10.1161/atvbaha.112.245381

Cited by 26 publications

(15 citation statements)

References 43 publications

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“…This results show that Tyr705 phosphorylation can be regulated indirectly by mTOR. It is known that a mTOR inhibitor cause compensatory activation of MAPKs signal [35,36]. And, It is also known that MAPKs regulate STAT3 activity, therefore, we considered that the inhibition of phosphorylation of STAT3 by everolimus mediate MAPKs pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The phosphorylation of p38 MAPK was increased by exposure to everolimus, and inhibition of phosphorylation of STAT3 Tyr705 by everolimus rescued by pretreatment of SB203580. mTOR inhibition by everolimus results in inhibition of de novo protein synthesis, and results in p38 MAPK activation due to sense cellular stress, moreover they may result in STAT3 inhibition [35]. We considered that p38 MAPK may be largely involved in the everolimus-induced inhibition of STAT3 activity in keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

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Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition

Yamamoto

Uda

Mukai

et al. 2013

J Exp Clin Cancer Res

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BackgroundMammalian target of rapamycin (mTOR) inhibitors are associated with dermatological adverse events. The chief aim of this study was to examine the relation between the signal transducer and activator of transcription 3 (STAT3) protein and the dermatological adverse events associated with the mTOR inhibitor everolimus.MethodsWe evaluated the effects of STAT3 activity and related signal transduction activities on everolimus-induced cell growth inhibition in the human keratinocyte HaCaT cell line via a WST-8 assay, and on signal transduction mechanisms involved in everolimus treatments via a western blot analysis. Apoptosis was evaluated using an imaging cytometric assay.ResultsThe cell growth inhibitory effects of everolimus were enhanced by stattic or STA-21, which are selective inhibitors of STAT3, treatment in HaCaT cells, although such effects were not observed in Caki-1 and HepG2 cells. Phosphorylation at tyrosine 705 of STAT3 was decreased by treatment with everolimus in a dose-dependent manner in HaCaT cells; in contrast, phosphorylation at serine 727 was not decreased by everolimus, but slightly increased. Furthermore, we found that pretreatment of p38 MAPK inhibitor and transfection with constitutively active form of STAT3 in HaCaT cells resisted the cytostatic activity of everolimus.ConclusionsThese findings suggest that STAT3 activity may be a biomarker of everolimus-induced dermatological toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition

Yamamoto

Uda

Mukai

et al. 2013

J Exp Clin Cancer Res

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“…However, stimulation of the autophagic pathway may also be detrimental. Induction of autophagy with toll-like receptor 7 ligands such as imiquimod or treatment with everolimus results in autophagy-independent increases in cytokine production, which could lead to induction of adhesion molecules, infiltration of inflammatory cells, and plaque enlargement [180, 181]. It appears that therapies for atherosclerosis targeting autophagy in macrophages are promising, but that the degree of autophagic activation would need to be tightly modulated to achieve a therapeutic window that reduces macrophage content in lesions.…”

Section: Autophagy In Vsmcsmentioning

confidence: 99%

Implications of autophagy for vascular smooth muscle cell function and plasticity

Salabei

Hill

2013

Free Radical Biology and Medicine

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Vascular smooth muscle cells (VSMCs) are fundamental in regulating blood pressure and distributing oxygen and nutrients to peripheral tissues. They also possess remarkable plasticity, with the capacity to switch to synthetic, macrophage-like or osteochondrogenic phenotypes when cued by external stimuli. In arterial diseases such as atherosclerosis and restenosis, this plasticity appears to be critical, and depending on the disease context, can be deleterious or beneficial. Therefore, understanding the mechanisms regulating VSMC phenotype and survival are essential for developing new therapies for vascular disease as well as understanding how secondary complications develop due to surgical interventions. In this regard, the cellular process of autophagy is increasingly being recognized as a major player in vascular biology and a critical determinant of VSMC phenotype and survival. Although autophagy was identified in lesional VSMCs in the 1960s, our understanding of the implications of autophagy in arterial diseases and the stimuli promoting its activation in VSMCs are only now being elucidated. In this review, we highlight the evidence for autophagy occurring in VSMCs in vivo, elaborate on the stimuli and processes regulating autophagy, and discuss the current understanding of the role of VSMC autophagy in vascular disease.

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“…Interestingly, inhibition of TOR activates MAPK to promote cell cycle progression in unicellular yeast [36] and mammalian cancer cell lines overcome TOR inhibition by activating ERK1/2 signaling [37], [38]. TOR inhibition also activates p38 signaling in megakaryocytes [39] and in glioblastoma cells [40]. The Mitogen and Stress Induced Kinase (MSK) has been identified as a common downstream effector of both ERK and p38 survival pathways [41].…”

Section: Introductionmentioning

confidence: 99%

Lifespan Extension in a Semelparous Chordate Occurs via Developmental Growth Arrest Just Prior to Meiotic Entry

2014

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It is proposed that the ageing process is linked to signaling from the germline such that the rate of ageing can be adjusted to the state of the reproductive system, allowing these two processes to co-evolve. Mechanistic insight into this link has been primarily derived from iteroparous reproductive models, the nematode C. elegans, and the arthropod Drosophila. Here, we examined to what extent these mechanisms are evolutionarily conserved in a semelparous chordate, Oikopleura dioica, where we identify a developmental growth arrest (GA) in response to crowded, diet-restricted conditions, which can extend its lifespan at least three-fold. Under nutritional stress, the iteroparative models sacrifice germ cells that have entered meiosis, while maintaining a reduced pool of active germline stem cells (GSCs). In contrast, O. dioica only entered GA prior to meiotic entry. Stress conditions encountered after this point led to maturation in a normal time frame but with reduced reproductive output. During GA, TOR signaling was inhibited, whereas MAPK, ERK1/2 and p38 pathways were activated, and under such conditions, activation of these pathways was shown to be critical for survival. Direct inhibition of TOR signaling alone was sufficient to prevent meiotic entry and germline differentiation. This inhibition activated the p38 pathway, but did not activate the ERK1/2 pathway. Thus, the link between reproductive status and lifespan extension in response to nutrient-limited conditions is interpreted in a significantly different manner in these iteroparative versus semelparous models. In the latter case, meiotic entry is a definitive signal that lifespan extension can no longer occur, whereas in the former, meiotic entry is not a unique chronological event, and can be largely erased during lifespan extension in response to nutrient stress, and reactivated from a pool of maintained GSCs when conditions improve.

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Everolimus Triggers Cytokine Release by Macrophages

Cited by 26 publications

References 43 publications

Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition

Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition

Implications of autophagy for vascular smooth muscle cell function and plasticity

Lifespan Extension in a Semelparous Chordate Occurs via Developmental Growth Arrest Just Prior to Meiotic Entry

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