Autophagy regulates the survival of cells with chromosomal instability.

Dawei Liu,Stephen Gregory,Donna Denton,Zeeshan Shaukat,Tianqi Xu,Robert Saint

doi:10.18632/oncotarget.11736

Abstract

Chromosomal instability (CIN) refers to genomic instability in which cells have gained or lost chromosomes or chromosomal fragments. A high level of CIN is common in solid tumours and is associated with cancer drug resistance and poor prognosis. The impact of CIN-induced stress and the resulting cellular responses are only just beginning to emerge. Using proliferating tissue in Drosophila as a model, we found that autophagy is activated in CIN cells and is necessary for their survival. Specifically, increasing the removal of defective mitochondria by mitophagy is able to lower levels of reactive oxygen species and the resultant cellular damage that is normally seen in CIN cells. In response to DNA damage, CIN is increased in a positive feedback loop, and we found that increasing autophagy by Tor depletion could decrease the level of CIN in proliferating cells. These findings underline the importance of autophagy control in the development of CIN tumours.

Highlights

Chromosomal instability (CIN) refers to the process by which cells are unable to maintain chromosomal integrity or number [1]
Stronger induction of autophagy was seen in rad21 CIN cells than in mad2 CIN cells (Figure 1A–1F), consistent with the higher level of CIN generated in the rad21 model [22]
As enhancing autophagic flux reduced the level of reactive oxygen species (ROS) (Figure 4), and we have previously shown that DNA damage in CIN cells is caused by elevated ROS [21], we wished to test whether increasing autophagy could moderate the CIN level

Summary

Introduction

Chromosomal instability (CIN) refers to the process by which cells are unable to maintain chromosomal integrity or number [1]. Autophagy is induced in response to various stresses to maintain metabolic homeostasis and prevent the buildup of dysfunctional cellular components [9]. The information currently available from clinical trials and mouse models suggests that a lack of autophagy predisposes tissue to develop tumours, possibly because autophagy normally moderates oxidative stress and DNA damage by removing defective mitochondria. The expectation is that tumours may need autophagy to tolerate the metabolic demands of proliferation, to avoid excessive oxidative stress and an unmanageable level of genome instability. Reduced autophagy may promote tumorigenesis by increasing DNA damage rates, but for tumours to thrive they may need to increase their autophagic flux to prevent deleterious levels of oxidative damage

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Results

Conclusion