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.
Highlights
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
Despite the fact that cyclin D1 is essentially known as an activator of the G1 phase of the cell cycle[9], we describe in this work that this protein is significantly upregulated during the initial step of chemotherapy-mediated senescence
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 sn[38] or doxorubicin
Summary
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. 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. 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. Cells that resist CIS grow in low adhesion conditions, form tumors in vivo and rely on Akt-Mcl-1 signaling In this experimental model, we concluded that the coexistence of senescent and dividing subclones favored cell emergence in response to chemotherapy. We have proposed that apoptosis is a superior suppressive mechanism as compared to CIS, at least in response to irinotecan
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