Akt1 and dCIZ1 promote cell survival from apoptotic caspase activation during regeneration and oncogenic overgrowth

Abstract

Apoptosis is an ancient and evolutionarily conserved cell suicide program. During apoptosis, executioner caspase enzyme activation has been considered a point of no return. However, emerging evidence suggests that some cells can survive caspase activation following exposure to apoptosis-inducing stresses, raising questions as to the physiological significance and underlying molecular mechanisms of this unexpected phenomenon. Here, we show that, following severe tissue injury, Drosophila wing disc cells that survive executioner caspase activation contribute to tissue regeneration. Through RNAi screening, we identify akt1 and a previously uncharacterized Drosophila gene CG8108, which is homologous to the human gene CIZ1, as essential for survival from the executioner caspase activation. We also show that cells expressing activated oncogenes experience apoptotic caspase activation, and that Akt1 and dCIZ1 are required for their survival and overgrowth. Thus, survival following executioner caspase activation is a normal tissue repair mechanism usurped to promote oncogene-driven overgrowth.

Integrin-specific hydrogels for growth factor-free vasculogenesis

“…Moreover, Akt was upregulated while no differences were observed for the phosphorylation of the ERK1/2 when αvβ3 integrin was blocked. Thus, the reduced secretion of VEGF might be linked to the overall need of cells to avoid apoptosis, as previously shown with the blockage of the αvβ3 integrin in ECs 45 , which in turn is in agreement with the activation of the Akt pathway, a critical regulator of PI3K-mediated cell survival 46 . While we do not demonstrate the direct involvement of VEGF, when the formation of VEGF-dependent vessels in a co-culture of pericytes and ECs is suppressed, pericytes activate the FGF pathway and start to express high levels of FGF-2 in a juxtacrine manner 47 .…”

On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm

“…The induction of PAMEs and PIMs are circumscribed in a wider set of responses to tissue damage and regulated cell death in multiple systems that include a cell-autonomous program for cell migration and the paracrine induction of compensatory or apoptosis-enhanced cell proliferation from adjacent cells (Pe ´rez- Garijo et al, 2004;Chera et al, 2009;Huang et al, 2011;Sun et 2020;rev. in Mollereau et al, 2013: Pinal et al, 2019.…”

“…Anti-cancer therapies with cell-death-inducing treatments (Longley et al, 2003;Comella et al, 2009;Carneiro and El-Deiry, 2020) can paradoxically enhance metastasis (Imamura et al, 1990;Wild-Bode et al, 2001;Poth et al, 2010;Vyas et al, 2014;Liu et al, 2015;Middleton et al, 2018;Karagiannis et al, 2019). How this comes about is not clear, although stemness acquisition, anastasis, senescence, and changes in the microen-vironment have all been proposed to contribute (Tang et al, 2012(Tang et al, , 2017Ding et al, 2016;Tato-Costa et al, 2016;Sun et al, 2017Sun et al, , 2020Xu et al, 2018;Middleton et al, 2018;Guillon et al, 2019;Berthenet et al, 2020). Cells surviving acute druginduced apoptosis can display oncogenic traits including epithelial-to-mesenchymal transition (EMT), the modulation of epigenetic remodelers, and limited migration (Tang et al, 2012;Ichim et al, 2015;Tato-Costa et al, 2016;Sun et al, 2017;Seervi et al, 2019;Berthenet et al, 2020).…”

Non-Apoptotic Role of Apoptotic Caspases in the Drosophila Nervous System

“…These reporters reveal many cell types, including those in the neuronal lineage, that activate apoptotic effector caspases but do not die during Drosophila development. An RNAi screen using a version of the CasExpress reporter identified genes that altered the number of living cells with past caspase activity ( Sun et al, 2020 ). Some of these genes act downstream of or in parallel to caspase activation to decide whether a cell that activated apoptotic caspases will survive or not.…”