Autophagy governs protumorigenic effects of mitotic slippage-induced senescence

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...

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Main Authors: Jakhar, Rekha, Luijten, Monique N. H., Wong, Alex X. F., Cheng, Bing, Guo, Ke, Neo, Suat P., Au, Bijin, Kulkarni, Madhura, Lim, Kah J., Maimaiti, Jiamila, Chong, Han Chung, Lim, Elaine H., Tan, Tee B. K., Ong, Kong W., Sim, Yirong, Wong, Jill S. L., Khoo, James B. K., Ho, Juliana T. S., Chua, Boon T., Sinha, Indrajit, Wang, Xiaomeng, Connolly, John E., Gunaratne, Jayantha, Crasta, Karen Carmelina
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2020
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Online Access:https://hdl.handle.net/10356/137179
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1371792020-11-01T05:12:19Z Autophagy governs protumorigenic effects of mitotic slippage-induced senescence Jakhar, Rekha Luijten, Monique N. H. Wong, Alex X. F. Cheng, Bing Guo, Ke Neo, Suat P. Au, Bijin Kulkarni, Madhura Lim, Kah J. Maimaiti, Jiamila Chong, Han Chung Lim, Elaine H. Tan, Tee B. K. Ong, Kong W. Sim, Yirong Wong, Jill S. L. Khoo, James B. K. Ho, Juliana T. S. Chua, Boon T. Sinha, Indrajit Wang, Xiaomeng Connolly, John E. Gunaratne, Jayantha Crasta, Karen Carmelina Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Chemotherapeutic Tumor Progression 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. NRF (Natl Research Foundation, S’pore) MOE (Min. of Education, S’pore) Accepted version 2020-03-05T03:16:32Z 2020-03-05T03:16:32Z 2018 Journal Article Jakhar, R., Lujiten, M. N. H., Wong, A. X. F., Cheng, B., Guo, K., Neo, S. P., . . . Crasta, K. C. (2018). Autophagy governs protumorigenic effects of mitotic slippage-induced senescence. Molecular cancer research, 16(11), 1625-1640. doi:10.1158/1541-7786.MCR-18-0024 1541-7786 https://hdl.handle.net/10356/137179 10.1158/1541-7786.MCR-18-0024 30037855 2-s2.0-85055906089 11 16 1625 1640 en Molecular cancer research © 2018 American Association for Cancer Research. All rights reserved. This paper was published in Molecular cancer research and is made available with permission of American Association for Cancer Research. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Chemotherapeutic
Tumor Progression
spellingShingle Science::Medicine
Chemotherapeutic
Tumor Progression
Jakhar, Rekha
Luijten, Monique N. H.
Wong, Alex X. F.
Cheng, Bing
Guo, Ke
Neo, Suat P.
Au, Bijin
Kulkarni, Madhura
Lim, Kah J.
Maimaiti, Jiamila
Chong, Han Chung
Lim, Elaine H.
Tan, Tee B. K.
Ong, Kong W.
Sim, Yirong
Wong, Jill S. L.
Khoo, James B. K.
Ho, Juliana T. S.
Chua, Boon T.
Sinha, Indrajit
Wang, Xiaomeng
Connolly, John E.
Gunaratne, Jayantha
Crasta, Karen Carmelina
Autophagy governs protumorigenic effects of mitotic slippage-induced senescence
description 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.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Jakhar, Rekha
Luijten, Monique N. H.
Wong, Alex X. F.
Cheng, Bing
Guo, Ke
Neo, Suat P.
Au, Bijin
Kulkarni, Madhura
Lim, Kah J.
Maimaiti, Jiamila
Chong, Han Chung
Lim, Elaine H.
Tan, Tee B. K.
Ong, Kong W.
Sim, Yirong
Wong, Jill S. L.
Khoo, James B. K.
Ho, Juliana T. S.
Chua, Boon T.
Sinha, Indrajit
Wang, Xiaomeng
Connolly, John E.
Gunaratne, Jayantha
Crasta, Karen Carmelina
format Article
author Jakhar, Rekha
Luijten, Monique N. H.
Wong, Alex X. F.
Cheng, Bing
Guo, Ke
Neo, Suat P.
Au, Bijin
Kulkarni, Madhura
Lim, Kah J.
Maimaiti, Jiamila
Chong, Han Chung
Lim, Elaine H.
Tan, Tee B. K.
Ong, Kong W.
Sim, Yirong
Wong, Jill S. L.
Khoo, James B. K.
Ho, Juliana T. S.
Chua, Boon T.
Sinha, Indrajit
Wang, Xiaomeng
Connolly, John E.
Gunaratne, Jayantha
Crasta, Karen Carmelina
author_sort Jakhar, Rekha
title Autophagy governs protumorigenic effects of mitotic slippage-induced senescence
title_short Autophagy governs protumorigenic effects of mitotic slippage-induced senescence
title_full Autophagy governs protumorigenic effects of mitotic slippage-induced senescence
title_fullStr Autophagy governs protumorigenic effects of mitotic slippage-induced senescence
title_full_unstemmed Autophagy governs protumorigenic effects of mitotic slippage-induced senescence
title_sort autophagy governs protumorigenic effects of mitotic slippage-induced senescence
publishDate 2020
url https://hdl.handle.net/10356/137179
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