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Title: Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs
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
Keywords: DRNTU::Science::Biological sciences
Multi-drug Resistance
Epithelial-mesenchymal Transition
Issue Date: 2018
Source: 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
Series/Report no.: Molecular Cancer
Abstract: 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.
DOI: 10.1186/s12943-018-0904-z
Rights: © 2018 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, 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 ( applies to the data made available in this article, unless otherwise stated
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
SBS Journal Articles

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