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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Main Authors: 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
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2019
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Online Access:https://hdl.handle.net/10356/103567
http://hdl.handle.net/10220/47340
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Institution: Nanyang Technological University
Language: English
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spelling 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
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences
Multi-drug Resistance
Epithelial-mesenchymal Transition
spellingShingle 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
description 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.
author2 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
author_sort 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
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