Format

Send to

Choose Destination
Mol Cancer Res. 2018 Nov;16(11):1625-1640. doi: 10.1158/1541-7786.MCR-18-0024. Epub 2018 Jul 23.

Autophagy Governs Protumorigenic Effects of Mitotic Slippage-induced Senescence.

Author information

1
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
2
Quantitative Proteomics Group, Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore.
3
Translational Immunology Group, Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore.
4
Acenzia Inc, Windsor, Ontario, Canada.
5
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
6
Division of Surgical Oncology, National Cancer Centre Singapore, Singapore.
7
Division of Oncologic Imaging, National Cancer Centre Singapore, Singapore.
8
Singapore Oncogenome Program, Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore.
9
Vascular Biology Group, Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore.
10
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
11
Institute of Biomedical Studies, Baylor University, Waco, Texas.
12
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
13
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. kccrasta@ntu.edu.sg.
14
School of Biological Sciences, Nanyang Technological University, Singapore.
15
Genomic Instability and Cancer Group, Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore.
16
Department of Medicine, Imperial College London, London, United Kingdom.
#
Contributed equally

Abstract

The most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and "slip" into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment.Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. Mol Cancer Res; 16(11); 1625-40. ©2018 AACR.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center