Myc Prevents Apoptosis and Enhances Endoreduplication Induced by Paclitaxel

Abstract

BackgroundThe role of the MYC oncogene in the apoptotic pathways is not fully understood. MYC has been reported to protect cells from apoptosis activation but also to sensitize cells to apoptotic stimuli. We have previously demonstrated that the down-regulation of Myc protein activates apoptosis in melanoma cells and increases the susceptibility of cells to various antitumoral treatments. Beyond the well-known role in the G1→S transition, MYC is also involved in the G2-M cell cycle phases regulation.Methodology/Principal FindingsIn this study we have investigated how MYC could influence cell survival signalling during G2 and M phases. We used the microtubules damaging agent paclitaxel (PTX), to arrest the cells in the M phase, in a p53 mutated melanoma cell line with modulated Myc level and activity. An overexpression of Myc protein is able to increase endoreduplication favoring the survival of cells exposed to antimitotic poisoning. The PTX-induced endoreduplication is associated in Myc overexpressing cells with a reduced expression of MAD2, essential component of the molecular core of the spindle assembly checkpoint (SAC), indicating an impairment of this checkpoint. In addition, for the first time we have localized Myc protein at the spindle poles (centrosomes) during pro-metaphase in different cell lines.ConclusionsThe presence of Myc at the poles during the prometaphase could be necessary for the Myc-mediated attenuation of the SAC and the subsequent induction of endoreduplication. In addition, our data strongly suggest that the use of taxane in antitumor therapeutic strategies should be rationally based on the molecular profile of the individual tumor by specifically analyzing Myc expression levels.

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G2 DNA Damage Checkpoint in Human Cancer Cells

“…5A; see Table S2 in the supplemental material). In response to TNF-␣, Calu-6 cells immediately activated a potent cell survival response, including the upregulation of prosurvival pathways such as BCL-x l , IL-6, Myc, and EGR (13,40,43) and also the downregulation of proapoptotic signaling components such as TRADD and FADD (Fig. 5B).…”

Low-dose paclitaxel downregulates MYC proto-oncogene bHLH transcription factor expression in colorectal carcinoma cells

“…A previous study has suggested that the use of PTX in antitumor therapeutic strategies should be rationally based on the molecular profile of the individual tumor by specifically analyzing Myc expression levels (23). Other anticancer drugs, including fluorouracil and niclosamide, have been reported to directly downregulate c-Myc expression in human colon cancer KM12C cells and human osteosarcoma cells, respectively (24,25).…”

Phosphorylation and stabilization of c-Myc by NEMO renders cells resistant to ionizing radiation through up-regulation of γ-GCS

“…c-Myc induces apoptosis and sensitizes cells to various apoptotic stimuli (12,15), but also has been reported to protect cells from apoptosis (6,8,10). In this study, we report that c-Myc, when it is phosphorylated and stabilized by NEMO, protects cells from IR-induced cell death.…”

“…Down-regulation of c-Myc increases susceptibility of M14 melanoma cells to cisplatin through reactive oxygen species (ROS)-mediated apoptosis and glutathione (GSH) depletion is a key factor in this apoptosis induction (6,7). c-Myc has also been reported to prevent paclitaxel-induced apoptosis by enhancing paclitaxelinduced endoreduplication (8). Sensitization of non-Hodgkin's lymphoma cells to ionizing radiation by rituximab is achieved through the inhibition of c-Myc expression (9).…”