ИСТИНА

Evading cell death is a major driving force for tumor progression that is one of the main problems in current cancer research. Mitotic catastrophe (MC) represents attractive platform compromising tumor resistance to current therapeutic modalities. MC appeared as onco-suppressive mechanism and is defined as a stage driving the cell to an irreversible destiny, i.e. cell death via apoptosis or necrosis. Our study highlights that MC induction in colon carcinoma cell lines by doxorubicin or colcemid ultimately leads to autophagy followed by apoptosis. The enhanced autophagic flux in HCT116 14-3-3σ-/- cells compared to wt HCT116 cells correlated with the MC rate. Both apoptosis and autophagy are regulated by a balance between pro- and anti-survival Bcl-2 family proteins. We found that this balance also modulates the outcome of MC. Overexpression of the anti-apoptotic Bcl-xL protein stimulated MC in wt cells in response to doxorubicin, whereas transfection with Mcl-1 attenuated MC, especially, in HCT116 14-3-3σ-/- cells. In HCT116 14-3-3σ-/- cells, transfection with Bcl-xL or Mcl-1 suppressed colcemid-induced MC. We show that autophagy suppression in Atg 13 knockout non-small cell lung carcinoma cells lead to the dramatic decrease of MC rate. Furthermore, mitochondria-linked anti-apoptotic proteins Mcl-1 and Bcl-xL play a crucial role in the duration of MC and a cross-talk between autophagy and apoptosis. Thus, the suppression of apoptosis by overexpression of Mcl-1 or Bcl-xL affected MC and lead to a significant induction of autophagy in HCT116 wt and 14-3-3σ-/- cells. Our data demonstrate that MC induction is a critical stage, in which a cell decides how to die, while mitochondria are responsible for the maintaining balance between MC – autophagy – apoptosis. Thus, autophagy stimulation after MC development represents a new approach to improving anti-cancer therapy.