Compensation between Wnt-driven tumorigenesis and cellular responses to ribosome biogenesis inhibition in the murine intestinal epithelium.
Aurélien RaveuxAline StedmanSabrina CoqueranSandrine Vandormael-PourninNick OwensBéatrice RomagnoloMichel Cohen-TannoudjiPublished in: Cell death and differentiation (2020)
Ribosome biogenesis inhibition causes cell cycle arrest and apoptosis through the activation of tumor suppressor-dependent surveillance pathways. These responses are exacerbated in cancer cells, suggesting that targeting ribosome synthesis may be beneficial to patients. Here, we characterize the effect of the loss-of-function of Notchless (Nle), an essential actor of ribosome biogenesis, on the intestinal epithelium undergoing tumor initiation due to acute Apc loss-of-function. We show that ribosome biogenesis dysfunction strongly alleviates Wnt-driven tumor initiation by restoring cell cycle exit and differentiation in Apc-deficient progenitors. Conversely Wnt hyperactivation attenuates the cellular responses to surveillance pathways activation induced by ribosome biogenesis dysfunction, as proliferation was maintained at control-like levels in the stem cells and progenitors of double mutants. Thus, our data indicate that, while ribosome biogenesis inhibition efficiently reduces cancer cell proliferation in the intestinal epithelium, enhanced resistance of Apc-deficient stem and progenitor cells to ribosome biogenesis defects may be an important concern when using a therapeutic strategy targeting ribosome production for the treatment of Wnt-dependent tumorigenesis.
Keyphrases
- cell proliferation
- stem cells
- cell cycle
- cell cycle arrest
- oxidative stress
- public health
- cell death
- ejection fraction
- newly diagnosed
- squamous cell carcinoma
- signaling pathway
- big data
- liver failure
- end stage renal disease
- young adults
- intensive care unit
- papillary thyroid
- deep learning
- drug delivery
- mesenchymal stem cells
- mouse model
- acute respiratory distress syndrome
- peritoneal dialysis
- respiratory failure
- childhood cancer