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

Abstract

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.

Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

“…In addition, some studies have preliminarily explored the mechanisms of AP2M1. Mélanie Le Duff et al [17] showed that the downregulation of AP2M1 in cancer cells signi cantly reduced the sensitivity to soluble signals generated from senescent cells, thereby inhibiting cell invasion. Further, following apoptosis induction, AP2M1 expression varies in different types of cells.…”

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

“…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).…”

Proteomics Approaches to Define Senescence Heterogeneity and Chemotherapy Response

“…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.…”

“…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. [16][17][18][19] 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. [20] This oncogenic activity of the SASP is normally restrained by Rb-Suv39 signaling or p53.…”

“…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. [16][17][18][19] Senescence escape leads to the emergence of more transformed clones with enhanced potential for migration. As stated above, following Suv39 inactivation, the Wnt pathway drives the dedifferentiation of senescent cells and the emergence of a subpopulation of more aggressive clones with higher tumor potential.…”