Please use this identifier to cite or link to this item: https://doi.org/10.1158/1541-7786.MCR-18-0024
Title: Autophagy governs protumorigenic effects of mitotic slippage-induced senescence
Authors: Jakhar, R
Luijten, M.N.H
Wong, A.X.F
Cheng, B
Guo, K
Neo, S.P
Au, B
Kulkarni, M
Lim, K.J
Maimaiti, J
Chong, H.C
Lim, E.H
Tan, T.B.K
Ong, K.W
Sim, Y
Wong, J.S.L 
Khoo, J.B.K
Ho, J.T.S 
Chua, B.T
Sinha, I
Wang, X
Connolly, J.E 
Gunaratne, J 
Crasta, K.C
Keywords: antimitotic agent
antineoplastic agent
autophagy related protein 5
biological marker
chloroquine
hydroxymethylglutaryl coenzyme A reductase kinase
nocodazole
paclitaxel
protein
protein p53
protein PERK
unclassified drug
AMP-activated protein kinase kinase
antineoplastic agent
cytokine
protein kinase
animal experiment
animal model
apoptosis
Article
autophagy
cancer inhibition
carcinogenesis
cell death
cell fate
cell invasion
cell migration
controlled study
DNA damage
endoplasmic reticulum stress
enzyme activation
escape behavior
G1 phase cell cycle checkpoint
gene silencing
human
human cell
human tissue
interphase
microtubule
mitosis
mitosis inhibition
mitotic slippage
mouse
nonhuman
paracrine signaling
phenotype
priority journal
S phase cell cycle checkpoint
senescence
tetraploidy
tumor growth
vascularization
animal
autophagy
Bagg albino mouse
bone tumor
cell aging
colon tumor
drug effect
female
genetic transfection
HCT 116 cell line
HEK293 cell line
MCF-7 cell line
metabolism
mitosis
neoplasm
nude mouse
osteosarcoma
pancreas tumor
pathology
physiology
xenograft
zebra fish
Animals
Antineoplastic Combined Chemotherapy Protocols
Autophagy
Bone Neoplasms
Cellular Senescence
Colonic Neoplasms
Cytokines
Female
HCT116 Cells
HEK293 Cells
Heterografts
Humans
MCF-7 Cells
Mice
Mice, Inbred BALB C
Mice, Nude
Mitosis
Neoplasms
Osteosarcoma
Pancreatic Neoplasms
Protein Kinases
Transfection
Zebrafish
Issue Date: 2018
Citation: Jakhar, R, Luijten, M.N.H, Wong, A.X.F, Cheng, B, Guo, K, Neo, S.P, Au, B, Kulkarni, M, Lim, K.J, Maimaiti, J, Chong, H.C, Lim, E.H, Tan, T.B.K, Ong, K.W, Sim, Y, Wong, J.S.L, Khoo, J.B.K, Ho, J.T.S, Chua, B.T, Sinha, I, Wang, X, Connolly, J.E, Gunaratne, J, Crasta, K.C (2018). Autophagy governs protumorigenic effects of mitotic slippage-induced senescence. Molecular Cancer Research 16 (11) : 1625-1640. ScholarBank@NUS Repository. https://doi.org/10.1158/1541-7786.MCR-18-0024
Rights: Attribution 4.0 International
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 senescenceassociated 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 Sphase 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. © 2018 American Association for Cancer Research.
Source Title: Molecular Cancer Research
URI: https://scholarbank.nus.edu.sg/handle/10635/181172
ISSN: 15417786
DOI: 10.1158/1541-7786.MCR-18-0024
Rights: Attribution 4.0 International
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