Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-10-01
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| Series: | Molecular Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12943-018-0904-z |
| _version_ | 1819027940013244416 |
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| author | Maegan Miang Kee Lim Jonathan Wei Kiat Wee Jen Chi Soong Damien Chua Wei Ren Tan Marco Lizwan Yinliang Li Ziqiang Teo Wilson Wen Bin Goh Pengcheng Zhu Nguan Soon Tan |
| author_facet | Maegan Miang Kee Lim Jonathan Wei Kiat Wee Jen Chi Soong Damien Chua Wei Ren Tan Marco Lizwan Yinliang Li Ziqiang Teo Wilson Wen Bin Goh Pengcheng Zhu Nguan Soon Tan |
| author_sort | Maegan Miang Kee Lim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T05:50:27Z |
| format | Article |
| id | doaj.art-31574e4da91348bdb307ddd59eba8376 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-21T05:50:27Z |
| publishDate | 2018-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-31574e4da91348bdb307ddd59eba83762022-12-21T19:13:59ZengBMCMolecular Cancer1476-45982018-10-011711810.1186/s12943-018-0904-zTargeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugsMaegan Miang Kee Lim0Jonathan Wei Kiat Wee1Jen Chi Soong2Damien Chua3Wei Ren Tan4Marco Lizwan5Yinliang Li6Ziqiang Teo7Wilson Wen Bin Goh8Pengcheng Zhu9Nguan Soon Tan10School of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeSchool of Biological Sciences, Nanyang Technological University SingaporeAbstract 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.http://link.springer.com/article/10.1186/s12943-018-0904-zEpithelial-mesenchymal transitionMulti-drug resistanceAngiopoietin-like 4ATP-binding cassette transporters |
| spellingShingle | Maegan Miang Kee Lim Jonathan Wei Kiat Wee Jen Chi Soong Damien Chua Wei Ren Tan Marco Lizwan Yinliang Li Ziqiang Teo Wilson Wen Bin Goh Pengcheng Zhu Nguan Soon Tan Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs Molecular Cancer Epithelial-mesenchymal transition Multi-drug resistance Angiopoietin-like 4 ATP-binding cassette transporters |
| title | 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_short | 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 |
| topic | Epithelial-mesenchymal transition Multi-drug resistance Angiopoietin-like 4 ATP-binding cassette transporters |
| url | http://link.springer.com/article/10.1186/s12943-018-0904-z |
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