Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs
Overcoming multidrug resistance has always been a major challenge in cancer treatment. Recent evidence suggested epithelial-mesenchymal transition plays a role in MDR, but the mechanism behind this link remains unclear. We found that the expression of multiple ABC transporters was elevated in concor...
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sg-ntu-dr.10356-1035672020-11-01T05:20:26Z Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs Lim, Maegan Miang Kee Wee, Jonathan Wei Kiat Soong, Jen Chi Chua, Damien Tan, Wei Ren Lizwan, Marco Li, Yinliang Teo, Ziqiang Goh, Wilson Wen Bin Zhu, Pengcheng Tan, Nguan Soon School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Biological sciences Multi-drug Resistance Epithelial-mesenchymal Transition Overcoming multidrug resistance has always been a major challenge in cancer treatment. Recent evidence suggested epithelial-mesenchymal transition plays a role in MDR, but the mechanism behind this link remains unclear. We found that the expression of multiple ABC transporters was elevated in concordance with an increased drug efflux in cancer cells during EMT. The metastasis-related angiopoietin-like 4 (ANGPTL4) elevates cellular ATP to transcriptionally upregulate ABC transporters expression via the Myc and NF-κB signaling pathways. ANGPTL4 deficiency reduced IC50 of anti-tumor drugs and enhanced apoptosis of cancer cells. In vivo suppression of ANGPTL4 led to higher accumulation of cisplatin-DNA adducts in primary and metastasized tumors, and a reduced metastatic tumor load. ANGPTL4 empowered cancer cells metabolic flexibility during EMT, securing ample cellular energy that fuels multiple ABC transporters to confer EMT-mediated chemoresistance. It suggests that metabolic strategies aimed at suppressing ABC transporters along with energy deprivation of EMT cancer cells may overcome drug resistance. MOE (Min. of Education, S’pore) Published version 2019-01-03T05:58:02Z 2019-12-06T21:15:34Z 2019-01-03T05:58:02Z 2019-12-06T21:15:34Z 2018 Journal Article Lim, M. M. K., Wee, J. W. K., Soong, J. C., Chua, D., Tan, W. R., Lizwan, M., ... Tan, N. S. (2018). Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs. Molecular Cancer, 17(1), 152-. doi:10.1186/s12943-018-0904-z https://hdl.handle.net/10356/103567 http://hdl.handle.net/10220/47340 10.1186/s12943-018-0904-z en Molecular Cancer © 2018 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated 8 p. application/pdf |
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DRNTU::Science::Biological sciences Multi-drug Resistance Epithelial-mesenchymal Transition Lim, Maegan Miang Kee Wee, Jonathan Wei Kiat Soong, Jen Chi Chua, Damien Tan, Wei Ren Lizwan, Marco Li, Yinliang Teo, Ziqiang Goh, Wilson Wen Bin Zhu, Pengcheng Tan, Nguan Soon Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs |
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Overcoming multidrug resistance has always been a major challenge in cancer treatment. Recent evidence suggested epithelial-mesenchymal transition plays a role in MDR, but the mechanism behind this link remains unclear. We found that the expression of multiple ABC transporters was elevated in concordance with an increased drug efflux in cancer cells during EMT. The metastasis-related angiopoietin-like 4 (ANGPTL4) elevates cellular ATP to transcriptionally upregulate ABC transporters expression via the Myc and NF-κB signaling pathways. ANGPTL4 deficiency reduced IC50 of anti-tumor drugs and enhanced apoptosis of cancer cells. In vivo suppression of ANGPTL4 led to higher accumulation of cisplatin-DNA adducts in primary and metastasized tumors, and a reduced metastatic tumor load. ANGPTL4 empowered cancer cells metabolic flexibility during EMT, securing ample cellular energy that fuels multiple ABC transporters to confer EMT-mediated chemoresistance. It suggests that metabolic strategies aimed at suppressing ABC transporters along with energy deprivation of EMT cancer cells may overcome drug resistance. |
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School of Biological Sciences |
author_facet |
School of Biological Sciences Lim, Maegan Miang Kee Wee, Jonathan Wei Kiat Soong, Jen Chi Chua, Damien Tan, Wei Ren Lizwan, Marco Li, Yinliang Teo, Ziqiang Goh, Wilson Wen Bin Zhu, Pengcheng Tan, Nguan Soon |
format |
Article |
author |
Lim, Maegan Miang Kee Wee, Jonathan Wei Kiat Soong, Jen Chi Chua, Damien Tan, Wei Ren Lizwan, Marco Li, Yinliang Teo, Ziqiang Goh, Wilson Wen Bin Zhu, Pengcheng Tan, Nguan Soon |
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Lim, Maegan Miang Kee |
title |
Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs |
title_short |
Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs |
title_full |
Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs |
title_fullStr |
Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs |
title_full_unstemmed |
Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs |
title_sort |
targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs |
publishDate |
2019 |
url |
https://hdl.handle.net/10356/103567 http://hdl.handle.net/10220/47340 |
_version_ |
1683493696296714240 |