The impact of cellular senescence in cancer therapy: is it true or not?

Zhang, Yi; Yang, Jin Ming

doi:10.1038/aps.2011.108

Cited by 23 publications

(16 citation statements)

References 85 publications

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“…Cell senescence can also be accelerated by the activation of oncogenes such as ras (6,7) or the inhibition of important biological pathways including the ubiquitin-proteasome system (UPS) (8). In the UPS, besides E1 activating enzymes and E2 conjugating enzymes, E3 ubiquitin ligases are the major enzymes that determine substrate specificity (9), leading to the modulation of specific signaling pathways through the ubiquitination of downstream targets.…”

Section: Introductionmentioning

confidence: 99%

The E3 ubiquitin ligase STUB1 attenuates cell senescence by promoting the ubiquitination and degradation of the core circadian regulator BMAL1

Ullah

Chen

Lü

et al. 2020

Journal of Biological Chemistry

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Cell senescence is one of the most important processes determining cell fate and is involved in many pathophysiological conditions, including cancer, neurodegenerative diseases, and other aging-associated diseases. It has recently been discovered that the E3 ubiquitin ligase STIP1 homology and U-box–containing protein 1 (STUB1 or CHIP) is up-regulated during the senescence of human fibroblasts and modulates cell senescence. However, the molecular mechanism underlying STUB1-controlled senescence is not clear. Here, using affinity purification and MS-based analysis, we discovered that STUB1 binds to brain and muscle ARNT-like 1 (BMAL1, also called aryl hydrocarbon receptor nuclear translocator–like protein 1 (ARNTL)). Through biochemical experiments, we confirmed the STUB1-BMAL1 interaction, identified their interaction domains, and revealed that STUB1 overexpression down-regulates BMAL1 protein levels through STUB1's enzymatic activity and that STUB1 knockdown increases BMAL1 levels. Further experiments disclosed that STUB1 enhances BMAL1 degradation, which is abolished upon proteasome inhibition. Moreover, we found that STUB1 promotes the formation of Lys-48–linked polyubiquitin chains on BMAL1, facilitating its proteasomal degradation. Interestingly, we also discovered that oxidative stress promotes STUB1 nuclear translocation and enhances its co-localization with BMAL1. STUB1 expression attenuates hydrogen peroxide–induced cell senescence, indicated by a reduced signal in senescence-associated β-gal staining and decreased protein levels of two cell senescence markers, p53 and p21. BMAL1 knockdown diminishes this effect, and BMAL1 overexpression abolishes STUB1's effect on cell senescence. In summary, the results of our work reveal that the E3 ubiquitin ligase STUB1 ubiquitinates and degrades its substrate BMAL1 and thereby alleviates hydrogen peroxide–induced cell senescence.

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Section: Introductionmentioning

confidence: 99%

The E3 ubiquitin ligase STUB1 attenuates cell senescence by promoting the ubiquitination and degradation of the core circadian regulator BMAL1

Ullah

Chen

Lü

et al. 2020

Journal of Biological Chemistry

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“…Although induction of accelerated senescence is considered a prospective strategy for therapy-induced senescence anticancer therapy, cancer cells remaining dormant in the senescent state can, for a long time, hold the potential for tumor relapse [4]. Cellular senescence may also contribute to the development of chemoresistance to anticancer drugs because chemotherapeutic agents are designed to target the actively proliferating cancer cells, and therefore, they are often ineffective in nondividing, senescent cells.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, senescent cells remain alive, metabolically active, and can eventually re-enter the mitotic cycle [3,4]. Induction of senescence in combination with conventional chemotherapy may be a potentially useful strategy to prevent re-entry of nondividing cells into the mitotic cycle.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of chemotherapeutic agents in glyceraldehyde-3-phosphate dehydrogenase-depleted human lung carcinoma A549 cells with the accelerated senescence phenotype

2013

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays a central role in glycolysis. Because cancer cells rely on aerobic glycolysis rather than oxidative phosphorylation, GAPDH-depleting agents have a therapeutic potential to impede cancer cell proliferation. Knockdown of GAPDH by RNA interference induced the accelerated senescent phenotype in A549 cells, suggesting that GAPDH is a potential molecular target for combination chemotherapy. The cytotoxic effects of a panel of anticancer drugs, 5-fluorouracil, 5-fluorouridine, 5-fluorodeoxyuridine, 6-thioguanine, cytarabine, fludarabine, cladribine, clofarabine, 2-chloroadenosine, and doxorubicin, were assessed in GAPDH-depleted A549 cells using a cell proliferation assay. GAPDH-depleted A549 cells, when compared with control cells, exhibited increased chemoresistance to several antimetabolite agents including cytarabine [inhibitory concentration 50 (IC50) 1.7±0.3 vs. 0.03±0.02 μmol/l], 2-chloroadenosine (IC50 7.1±1.8 vs. 1.5±0.6 μmol/l), 6-thioguanine (IC50 7.5±1.6 vs. 1.4±0.5 μmol/l), 5-fluorouracil (IC50 13.2±2.5 vs. 3.0±0.7 μmol/l), and 5-fluorodeoxyuridine (IC50 >100 vs. 3.7±0.9 μmol/l), which we designated as group A agents. In contrast, GAPDH-deficient and GAPDH-proficient cells were equally sensitive to group B agents including doxorubicin (IC50 0.05±0.02 vs. 0.04±0.02 μmol/l), fludarabine (IC50 18.5±2.3 vs. 15.7±2.8 μmol/l), 5-fluorouridine (IC50 0.1±0.03 vs. 0.1±0.03 μmol/l), clofarabine (IC50 0.7±0.3 vs. 0.5±0.3 μmol/l), and cladribine (IC50 0.5±0.1 vs. 0.5±0.2 μmol/l). After treatment with group B agents at concentrations equivalent to 7-10-fold the IC50 value, the fraction of apoptotic cells in GAPDH-depleted, senescent A549 cells was similar to that in GAPDH-proficient cells. Our study identified the antimetabolite drugs active in senescent cells that can be used in combination with GAPDH inhibitors in cancer treatment. GAPDH-targeted combination therapy is a novel strategy to control the proliferation of tumor cells.

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“…Various anticancer drugs function by inducing intrinsic and extrinsic apoptosis in tumor cells 88 . The cellular response to apoptotic signaling can determine the outcome of treatment.…”

Section: Micrornas Influence Therapeutic-induced Cell Deathmentioning

confidence: 99%

Friend or foe: the role of microRNA in chemotherapy resistance

Yang

2013

Acta Pharmacol Sin

106

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Chemotherapy has been widely used in treating cancer patients. Despite the tremendous progress in cancer treatment achieved during the last decades, drug resistance still accounts for most of the tumor relapses in chemotherapy-treated patients. Emerging evidence shows that microRNAs play an important role in regulating the drug sensitivity of tumor cells. However, the mechanism of microRNA-mediated drug resistance is not fully understood. Current data suggest that microRNAs can be categorized as oncogenic or tumor-suppressive based on their functions and targets. In tumor cells undergoing drug treatment, microRNAs can function either by decreasing expression of genes associated with multiple drug resistance or by promoting escape from apoptosis and inducing tumor stem cell development. This review aims to provide an updated understanding of the role of microRNAs in regulating chemotherapy resistance and a discussion of potential therapeutic applications.

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The impact of cellular senescence in cancer therapy: is it true or not?

Cited by 23 publications

References 85 publications

The E3 ubiquitin ligase STUB1 attenuates cell senescence by promoting the ubiquitination and degradation of the core circadian regulator BMAL1

The E3 ubiquitin ligase STUB1 attenuates cell senescence by promoting the ubiquitination and degradation of the core circadian regulator BMAL1

Cytotoxicity of chemotherapeutic agents in glyceraldehyde-3-phosphate dehydrogenase-depleted human lung carcinoma A549 cells with the accelerated senescence phenotype

Friend or foe: the role of microRNA in chemotherapy resistance

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