Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment
Aberrant lipid accumulation is a hallmark of cancer known to contribute to its aggressiveness and malignancy. Emerging studies have demonstrated context-dependent changes in lipid metabolism during chemotherapy. However, there is little known regarding the mechanisms linking lipid metabolism to chem...
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sg-ntu-dr.10356-1431912020-11-01T05:10:19Z Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment Wong, Alex Chen, Sixun Yang, Lay Kien Kanagasundaram, Yoganathan Crasta, Karen Carmelina Interdisciplinary Graduate School (IGS) Lee Kong Chian School of Medicine (LKCMedicine) Institute for Health Technologies Science::Medicine Lipid Drug Treatment Aberrant lipid accumulation is a hallmark of cancer known to contribute to its aggressiveness and malignancy. Emerging studies have demonstrated context-dependent changes in lipid metabolism during chemotherapy. However, there is little known regarding the mechanisms linking lipid metabolism to chemotherapy-induced cell fates. Here, we describe lipid accumulation in cells following antimitotic drug treatment. Cells arrested in mitosis, as well as cells that escaped mitotic arrest and underwent mitotic slippage, showed elevated cytoplasmic lipid droplets. Interestingly, we found that TOFA, a lipid biosynthesis inhibitor that targets acetyl-CoA carboxylase (ACC) and blocks lipid accumulation, promoted early slippage, reduced cellular stress and enhanced survival of antimitotic-treated cells. Our work previously revealed that cells that survive after mitotic slippage can become senescent and confer pro-tumourigenic effects through paracrine signalling. Modulating lipid biosynthesis in cells post slippage by TOFA amplified their inflammatory secretion profiles and accelerated the development of tumourigenic behaviour, particularly cell migration and invasion, in a paracrine-dependent manner. In contrast to TOFA, inhibition of lipid accumulation by C75, a drug targeting fatty acid synthase (FASN), significantly reduced the production of pro-tumourigenic factors and associated phenotypic effects. This suggests that discrete lipid biosynthesis pathways could contribute differentially to the regulation of pro-tumourigenic inflammation. The divergent effects of TOFA and C75 may be attributed to the opposing regulation of Malonyl-CoA, an intermediate in fatty acid synthesis that serves as a mediator of fatty acid oxidation. Taken together, our data reveal a previously unappreciated role for lipid accumulation in the cellular adaptation to antimitotic drug treatment. Targeting lipid biosynthesis in cells post slippage may reprogramme its secretory profile such that it not only negates tumour-promoting effects, but may also promote anti-tumour inflammation for clearance of post-slippage senescent cells. Published version 2020-08-12T00:57:07Z 2020-08-12T00:57:07Z 2018 Journal Article Wong, A., Chen, S., Yang, L. K., Kanagasundaram, Y., & Crasta, K. C. (2018). Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment. Cell Death Discovery, 4(1), 109-. doi:10.1038/s41420-018-0127-5 2058-7716 https://hdl.handle.net/10356/143191 10.1038/s41420-018-0127-5 30510774 2-s2.0-85070946850 1 4 en Cell Death Discovery © 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. application/pdf |
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Science::Medicine Lipid Drug Treatment Wong, Alex Chen, Sixun Yang, Lay Kien Kanagasundaram, Yoganathan Crasta, Karen Carmelina Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment |
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Aberrant lipid accumulation is a hallmark of cancer known to contribute to its aggressiveness and malignancy. Emerging studies have demonstrated context-dependent changes in lipid metabolism during chemotherapy. However, there is little known regarding the mechanisms linking lipid metabolism to chemotherapy-induced cell fates. Here, we describe lipid accumulation in cells following antimitotic drug treatment. Cells arrested in mitosis, as well as cells that escaped mitotic arrest and underwent mitotic slippage, showed elevated cytoplasmic lipid droplets. Interestingly, we found that TOFA, a lipid biosynthesis inhibitor that targets acetyl-CoA carboxylase (ACC) and blocks lipid accumulation, promoted early slippage, reduced cellular stress and enhanced survival of antimitotic-treated cells. Our work previously revealed that cells that survive after mitotic slippage can become senescent and confer pro-tumourigenic effects through paracrine signalling. Modulating lipid biosynthesis in cells post slippage by TOFA amplified their inflammatory secretion profiles and accelerated the development of tumourigenic behaviour, particularly cell migration and invasion, in a paracrine-dependent manner. In contrast to TOFA, inhibition of lipid accumulation by C75, a drug targeting fatty acid synthase (FASN), significantly reduced the production of pro-tumourigenic factors and associated phenotypic effects. This suggests that discrete lipid biosynthesis pathways could contribute differentially to the regulation of pro-tumourigenic inflammation. The divergent effects of TOFA and C75 may be attributed to the opposing regulation of Malonyl-CoA, an intermediate in fatty acid synthesis that serves as a mediator of fatty acid oxidation. Taken together, our data reveal a previously unappreciated role for lipid accumulation in the cellular adaptation to antimitotic drug treatment. Targeting lipid biosynthesis in cells post slippage may reprogramme its secretory profile such that it not only negates tumour-promoting effects, but may also promote anti-tumour inflammation for clearance of post-slippage senescent cells. |
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Interdisciplinary Graduate School (IGS) |
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Interdisciplinary Graduate School (IGS) Wong, Alex Chen, Sixun Yang, Lay Kien Kanagasundaram, Yoganathan Crasta, Karen Carmelina |
format |
Article |
author |
Wong, Alex Chen, Sixun Yang, Lay Kien Kanagasundaram, Yoganathan Crasta, Karen Carmelina |
author_sort |
Wong, Alex |
title |
Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment |
title_short |
Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment |
title_full |
Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment |
title_fullStr |
Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment |
title_full_unstemmed |
Lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment |
title_sort |
lipid accumulation facilitates mitotic slippage-induced adaptation to anti-mitotic drug treatment |
publishDate |
2020 |
url |
https://hdl.handle.net/10356/143191 |
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1683492970977820672 |