Inhibition of nuclear factor-erythroid 2–related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence

Volonté, Daniela; Liu, Zhongmin; Musille, Paul M.; Stoppani, Elena; Wakabayashi, Nobunao; Di, Y. Peter; Lisanti, Michael P.; Kensler, Thomas W.; Galbiati, Ferruccio

doi:10.1091/mbc.e12-09-0666

Cited by 109 publications

(87 citation statements)

References 47 publications

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“…2, A and B). However, Sirt1 strongly interacted with caveolin-1 72 h after stimulation of WI-38 cells with sublethal doses of hydrogen peroxide, which, as we have shown previously, induces premature senescence (32)(33)(34)(35)(36)(37)(38) (Fig. 2, A and B).…”

Section: Caveolin-1 Bindssupporting

confidence: 75%

“…Our laboratory was the first to show that caveolin-1 is a key mediator of the signaling events underlying oxidative stress-induced premature senescence (32)(33)(34)(35)(36)(37)(38). We demonstrated that disruption of caveolae inhibits SIPS both in cell culture models and in vivo (32)(33)(34)(35)(36)(37)(38). Here we investigated the molecular mechanisms through which caveolin-1 links free radicals to the protumorigenic properties of cellular senescence.…”

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confidence: 98%

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Oxidative Stress-induced Inhibition of Sirt1 by Caveolin-1 Promotes p53-dependent Premature Senescence and Stimulates the Secretion of Interleukin 6 (IL-6)

Volonté¹,

Zou²,

Bartholomew³

et al. 2015

Journal of Biological Chemistry

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Background: Oxidative stress promotes premature senescence in eukaryotic cells. Results: Inhibition of Sirt1 by caveolin-1 is induced by free radicals and promotes cellular senescence and secretion of tumorigenic IL-6 in fibroblasts. Conclusion:The caveolin-1/Sirt1/IL-6 signaling pathway contributes to explain the ability of senescent cells to stimulate cancer cell growth. Significance: This novel signaling cascade brings new insights into how senescent cells regulate the tissue microenvironment.

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Section: Caveolin-1 Bindssupporting

confidence: 75%

mentioning

confidence: 98%

Oxidative Stress-induced Inhibition of Sirt1 by Caveolin-1 Promotes p53-dependent Premature Senescence and Stimulates the Secretion of Interleukin 6 (IL-6)

Volonté¹,

Zou²,

Bartholomew³

et al. 2015

Journal of Biological Chemistry

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“…For example, alkaloid trigonelline, an inhibitor of Nrf2, renders pancreatic cancer more susceptible to apoptosis (49); ochratoxin inhibits the Nrf2 oxidative stress response pathway (50); and brusatol increases intracellular ROS sensitizing mammospheres to taxol (51). Thus, an Nrf2 inhibitor or the inhibition of Nrf2 by increasing the expression of caveolin (52) may be of therapeutic benefit in all TTF1-negative LUAD.…”

Section: Discussionmentioning

confidence: 99%

An Integrated Molecular Analysis of Lung Adenocarcinomas Identifies Potential Therapeutic Targets among TTF1-Negative Tumors, Including DNA Repair Proteins and Nrf2

Cardnell

Behrens

Diao

et al. 2015

Clinical Cancer Research

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Purpose Thyroid transcription factor-1 (TTF1) immunohistochemistry (IHC) is used clinically to differentiate primary lung adenocarcinomas (LUAD) from squamous lung cancers and metastatic adenocarcinomas from other primary sites. However, a subset of LUAD (15-20%) does not express TTF1 and TTF1-negative patients have worse clinical outcomes. As there are no established targeted agents with activity in TTF1-negative LUAD, we performed an integrated molecular analysis to identify potential therapeutic targets. Experimental Design Using two clinical LUAD cohorts (274 tumors), one from our institution (PROSPECT) and the TCGA, we interrogated proteomic profiles (by reverse-phase protein array (RPPA)), gene expression, and mutational data. Drug response data from 74 cell lines were used to validate potential therapeutic agents. Results Strong correlations were observed between TTF1 IHC and TTF1 measurements by RPPA (Rho=0.57, p<0.001) and gene expression (NKX2-1, Rho=0.61, p<0.001). Established driver mutations (e.g. BRAF and EGFR) were associated with high TTF1 expression. In contrast, TTF1-negative LUAD had a higher frequency of inactivating KEAP1 mutations (p=0.001). Proteomic profiling identified increased expression of DNA repair proteins (e.g., Chk1 and the DNA repair score) and suppressed PI3K/MAPK signaling among TTF1-negative tumors, with differences in total proteins confirmed at the mRNA level. Cell line analysis showed drugs targeting DNA repair to be more active in TTF1-low cell lines. Conclusions Combined genomic and proteomic analyses demonstrated infrequent alteration of validated lung cancer targets (including the absence of BRAF mutations in TTF1-negative LUAD), but identified novel potential targets for TTF1-negative LUAD includingKEAP1/Nrf2 and DNA repair pathways.

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“…For example, a decrease in both Nrf2 protein and mRNA levels (~65% and 45%, respectively) was found in senescent fibroblasts relative to their presenescent counterparts, and expression of several target genes decreased as well. Similarly, inhibition of Nrf2 by caveolin‐1 promotes stress‐induced premature senescence (Volonte et al ., 2013). Furthermore, silencing the Nrf2 pathway in human embryonic fibroblasts leads to premature senescence (Kapeta et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

et al. 2017

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SummarySenescent cells contribute to age‐related pathology and loss of function, and their selective removal improves physiological function and extends longevity. Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species. Nrf2 levels have been shown to decrease with aging and silencing Nrf2 gene induces premature senescence. Therefore, we explored whether Nrf2 is involved in the mechanism by which rapamycin delays cell senescence. In wild‐type (WT) mouse fibroblasts, rapamycin increased the levels of Nrf2, and this correlates with the activation of autophagy and a reduction in the induction of cell senescence, as measured by SA‐β‐galactosidase (β‐gal) staining, senescence‐associated secretory phenotype (SASP), and p16 and p21 molecular markers. In Nrf2KO fibroblasts, however, rapamycin still decreased β‐gal staining and the SASP, but rapamycin did not activate the autophagy pathway or decrease p16 and p21 levels. These observations were further confirmed in vivo using Nrf2KO mice, where rapamycin treatment led to a decrease in β‐gal staining and pro‐inflammatory cytokines in serum and fat tissue; however, p16 levels were not significantly decreased in fat tissue. Consistent with literature demonstrating that the Stat3 pathway is linked to the production of SASP, we found that rapamycin decreased activation of the Stat3 pathway in cells or tissue samples from both WT and Nrf2KO mice. Our data thus suggest that cell senescence is a complex process that involves at least two arms, and rapamycin uses Nrf2 to regulate cell cycle arrest, but not the production of SASP.

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Inhibition of nuclear factor-erythroid 2–related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence

Abstract: Reactive oxygen species can induce premature senescence. Caveolin-1 promotes oxidative stress–induced activation of the p53/p21Waf1/Cip1 pathway and development of premature senescence by acting as an endogenous inhibitor of the transcription factor Nrf2.

Cited by 109 publications

References 47 publications

Oxidative Stress-induced Inhibition of Sirt1 by Caveolin-1 Promotes p53-dependent Premature Senescence and Stimulates the Secretion of Interleukin 6 (IL-6)

Oxidative Stress-induced Inhibition of Sirt1 by Caveolin-1 Promotes p53-dependent Premature Senescence and Stimulates the Secretion of Interleukin 6 (IL-6)

An Integrated Molecular Analysis of Lung Adenocarcinomas Identifies Potential Therapeutic Targets among TTF1-Negative Tumors, Including DNA Repair Proteins and Nrf2

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

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