Akt inhibition improves irinotecan treatment and prevents cell emergence by switching the senescence response to apoptosis

Vétillard, Alexandra; Jonchère, Barbara; Moreau, Marie; Toutain, Bertrand; Henry, Cécile; Fontanel, Simon; Bernard, Anne-Charlotte; Campone, Mario; Guette, Catherine; Coqueret, Olivier

doi:10.18632/oncotarget.6126

Cited by 28 publications

(40 citation statements)

References 54 publications

(82 reference statements)

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“…We have recently described that subpopulations of colorectal cells can escape CIS and resume proliferation 7 , 8 , 11 . This was confirmed in this study using either colorectal cut at colo-rectal with the pdf margin instead of color-ectal (LS174T) or breast (MCF7) cancer cells that entered senescence when treated respectively with sn38 or doxorubicin.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, phosphatase and tensin homolog (PTEN) depletion reverses established senescence induced by the BRAF oncogene and this leads to tumor progression 4 . In colorectal cancer, we have recently described two models of senescence escape, in response to oncogene 5 , 6 or during chemotherapy-induced senescence (CIS) 7 , 8 . In both cases, we have observed that a subpopulation of cells escapes this arrest and emerges as a more aggressive, dividing population.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of senescence escape by the cdk4–EZH2–AP2M1 pathway in response to chemotherapy

et al. 2018

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Senescence is a tumor suppressive mechanism that induces a permanent proliferative arrest in response to an oncogenic insult or to the genotoxic stress induced by chemotherapy. We have recently described that some cells can escape this arrest, either because senescence was incomplete or as a consequence of a phenotypic adaptation. Malignant cells which resisted senescence emerged as more transformed cells that resist anoikis and rely on survival pathways activated by Akt and Mcl-1. In this study, we further characterize senescence escape, investigating how emergent cells could reproliferate. During the initial step of chemotherapy-induced senescence (CIS), we found that cyclin D1 was upregulated and that cell emergence was prevented when its main partner cdk4 was inactivated. Results indicate that this kinase induced the upregulation of the EZH2 methylase, a component of the polycomb PRC2 complex. Downregulated during the early step of treatment, the methylase was reactivated in clones that escaped senescence. The inactivation of EZH2, either by siRNA or by specific inhibitors, led to a specific inhibition of cell emergence. We used quantitative proteomic analysis to identify new targets of the methylase involved in senescence escape. We identified proteins involved in receptor endocytosis and described new functions for the AP2M1 protein in the control of chemotherapy-mediated senescence. Our results indicate that AP2M1 is involved in the transmission of secreted signals produced by senescent cells, suggesting that this pathway might regulate specific receptors involved in the control of CIS escape. In light of these results, we therefore propose that the cdk4–EZH2–AP2M1 pathway plays an important role during chemotherapy resistance and senescence escape. Since targeted therapies are available against these proteins, we propose that they should be tested in the treatment of colorectal or breast cancers that become resistant to first-line genotoxic therapies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of senescence escape by the cdk4–EZH2–AP2M1 pathway in response to chemotherapy

et al. 2018

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“…These deleterious effects are not limited to carcinogenesis. We and others have also shown that these arrested cells and the proteins they secrete play a key role in chemotherapy resistance, allowing the generation of more aggressive cells in response to genotoxic treatments . For instance, important results indicate that Wnt activation induces the dedifferentiation of senescent cells, the reactivation of cell cycle progression, and the generation of subpopulations with higher tumor initiation potential .…”

Section: The Senescence‐associated Secretory Phenotypementioning

confidence: 95%

“…In this condition, we and others have shown that senescence relies on p21waf1 and it is not obvious that this protein is always acting as an inhibitor of cancer progression. Using different experimental models, we have shown that cancer cells enter senescence in response to chemotherapy but that persistent cells are able to escape this suppressive arrest . Senescence escape leads to the emergence of more transformed clones with enhanced potential for migration.…”

Section: Different Outcomes For Different Senescence Typesmentioning

confidence: 99%

Proteomics Approaches to Define Senescence Heterogeneity and Chemotherapy Response

et al. 2019

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In primary cells, senescence induces a permanent proliferative arrest to prevent the propagation of malignant cells. However, the outcome of senescence is more complex in advanced cancer cells where senescent states are heterogeneous. Here, this heterogeneity is discussed and it is proposed that proteomic analysis should be used to identify specific signatures of cancer cells that use this pathway as an adaptive mechanism. Since senescent cells produce an inflammatory secretome, MRM approaches and quantification with internal standards might be particularly suited to follow the expression of the corresponding markers in body fluids. Used in combination with imaging medical technics, a better characterization of senescence heterogeneity should help to monitor the response to chemotherapy treatment.

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“…We and others have shown that this suppression functions as an adaptive mechanism in response to chemotherapy-induced -senescence (CIS) (7,9). We have described that cancer cells can escape senescence and emerge as more transformed cells that resist anoikis and are more invasive (14)(15)(16)(17). In addition, we have also shown that cells having an incomplete senescence response are characterized by a reduced expression of CD47 (17).…”

Section: Introductionmentioning

confidence: 93%

tRNA Biogenesis and Specific Aminoacyl-tRNA Synthetases Regulate Senescence Stability Under the Control of mTOR

Guillon

Toutain

Boissard

et al. 2020

Preprint

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Running title: tRNA deregulation during senescence ABSTRACT Senescence normally prevents the propagation of abnormal cells but is also associated with cancer progression and chemotherapy resistance. These contradictory effects are related to the stability of epigenetic marks and to the senescence-associated secretory phenotype (SASP). The SASP reinforces the proliferative arrest but also induces tumor growth and inflammation during aging. S e n e s c e n c e i s t h e r e f o r e m u c h m o r e heterogeneous than initially thought. How this response varies is not really understood.Using experimental models of senescence escape, we now described that the deregulation of tRNA biogenesis affects the stability of this suppression, leading to chemotherapy resistance. Proteomic analyses showed that several aminoacyl-tRNA synthetases were down-regulated in senescent cells. tRNA transcription was also inhibited as a consequence of a reduced DNA binding of the type III RNA polymerase. Reducing RNA Pol III activity by BRF1 depletion maintained senescence and blocked cell persistence. Results showed that the YA R S 1 a n d L A R S 1 a m i n o a c y l -t R N A synthetases were necessary for cell emergence and that their corresponding tRNA-Leu-CAA and tRNA-Tyr-GTA were up-regulated in persistent cells. On the contrary, the CARS1 ligase had no effect on persistence and the expression of the corresponding tRNA-Cys was not modified. Results also showed that these tRNAs were regulated by mTOR and that this abnormal tRNA biogenesis induced an ER stress which was resolved by the kinase during chemotherapy escape.Overall, these findings highlight a new regulation of tRNA biology during senescence and suggest that specific tRNAs and ligases contribute to the strength and heterogeneity of this suppression and to chemotherapy resistance.

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Akt inhibition improves irinotecan treatment and prevents cell emergence by switching the senescence response to apoptosis

Cited by 28 publications

References 54 publications

Regulation of senescence escape by the cdk4–EZH2–AP2M1 pathway in response to chemotherapy

Regulation of senescence escape by the cdk4–EZH2–AP2M1 pathway in response to chemotherapy

Proteomics Approaches to Define Senescence Heterogeneity and Chemotherapy Response

tRNA Biogenesis and Specific Aminoacyl-tRNA Synthetases Regulate Senescence Stability Under the Control of mTOR

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