Involvement of autophagy in the outcome of mitotic catastrophe

Irina V Sorokina,Vladimir Gogvadze,Gabriela Imreh,Tatiana V Denisenko,Pyotr A Tyurin-Kuzmin,Vitaliy O Kaminskyy,Boris Zhivotovsky

doi:10.1038/s41598-017-14901-z

Irina V Sorokina, Vladimir Gogvadze + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-14901-z

Copy DOI

Abstract

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 colorectal carcinoma cell lines ultimately leads to the autophagy followed by apoptosis. 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 HCT116 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 the balance between MC – autophagy – apoptosis.

Highlights

The elimination of tumor cells by commonly used anticancer drugs is mediated by triggering cell death, predominantly apoptosis, autophagy or necroptosis
The inhibition of checkpoint kinase 2 (Chk2) or the absence of the cell cycle regulator 14-3-3σ was found to facilitate the translocation of the cyclin-dependent kinase 1 (CDK1) – cyclin-B complex to the nucleus, thereby, preventing G2 arrest and triggering mitotic catastrophe (MC) because of entry into mitosis with unrepaired DNA
Since MC can lead to both apoptosis and autophagy, we investigated whether mitochondria are involved in regulation of this balance

Summary

Introduction

The elimination of tumor cells by commonly used anticancer drugs is mediated by triggering cell death, predominantly apoptosis, autophagy or necroptosis. The failure to undergo cell death in response to anticancer therapy can result in drug resistance that is a major problem limiting the effectiveness of anticancer treatment[1,2]. Recent studies have suggested that, similar to apoptosis, autophagy might act as an important mechanism for the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. 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

Methods

Results

Conclusion