Failed apoptosis enhances melanoma cancer cells aggressiveness

Abstract

Triggering apoptosis remains an efficient strategy to treat cancer. However, apoptosis is no longer a final destination, since cells can undergo partial apoptosis without dying. Recent evidence shows that partial mitochondrial permeabilization and non-lethal caspase activation occur under certain circumstances, though it remains unclear how failed apoptosis impacts established cancers. Using a cancer cell model to trigger non-lethal caspase activation based on either BH3-only protein expression or chemotherapy treatment, we found that melanoma cancer cells failing to undergo complete apoptosis have a particular transcriptomic signature associated with focal adhesions, transendothelial migration and modifications of actin cytoskeleton.In line with this, cancer cells surviving apoptosis have a gain in migratory and invasive properties both in vitro (random migration, chemotaxis, wound healing and invasion assays) and in vivo (in a model of zebrafish metastasis)We further demonstrate that the failed apoptosis-associated gain in invasiveness is regulated by the c-Jun N-terminal kinase (JNK) pathway while its RNA seq signature is found in metastatic melanoma. These findings are highly significant for understanding how cell death can both cure and promote cancer.3

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

“…Cultured mammalian cells can recover from executioner caspase activation induced by transient exposure to apoptotic inducers like ethanol, staurosporine, and TNFα, through a process called anastasis 3,4,6 . Similar events have been described in tumors cells after tBid overexpression 5 or treatment with chemotherapeutic drugs like paclitaxel 8 . Survival after stress-induced executioner caspase activation has also been reported in cardiomyocytes after ischemia-reperfusion 9 and in neurons expressing pathogenic tau 10 in mice.…”

“…Executioner caspase activation has thus been considered a point of no return 2 . However, recent studies show that some cells can survive apoptosis-inducing stresses even after executioner caspase activation [3][4][5][6][7][8] . Cultured mammalian cells can recover from executioner caspase activation induced by transient exposure to apoptotic inducers like ethanol, staurosporine, and TNFα, through a process called anastasis 3,4,6 .…”