iRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation

Fatty acid oxidation (FAO) plays a vital role in drug resistance in cancer cells. Carnitine palmitoyltransferase 1A (CPT1A), a key enzyme of FAO, is widely recognized as an emerging therapeutic target. Here, we confirmed that CPT1A was heterogeneously expressed in colon cancer cells, with a high exp...

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Autores principales:	Dan Lin, Haiyang Zhang, Rui Liu, Ting Deng, Tao Ning, Ming Bai, Yuchong Yang, Kegan Zhu, Junyi Wang, Jingjing Duan, Shaohua Ge, Bei Sun, Guoguang Ying, Yi Ba
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	chemoresistance colon cancer exosomes FAO iRGD oxaliplatin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/0c60783763d74dd89591e440358a62b7
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spelling	oai:doaj.org-article:0c60783763d74dd89591e440358a62b72021-12-02T10:31:06ZiRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation1878-02611574-789110.1002/1878-0261.13052https://doaj.org/article/0c60783763d74dd89591e440358a62b72021-12-01T00:00:00Zhttps://doi.org/10.1002/1878-0261.13052https://doaj.org/toc/1574-7891https://doaj.org/toc/1878-0261Fatty acid oxidation (FAO) plays a vital role in drug resistance in cancer cells. Carnitine palmitoyltransferase 1A (CPT1A), a key enzyme of FAO, is widely recognized as an emerging therapeutic target. Here, we confirmed that CPT1A was heterogeneously expressed in colon cancer cells, with a high expression in oxaliplatin‐resistant cells but low expression in oxaliplatin‐sensitive cells, and expression could be increased by oxaliplatin stimulation. In addition, we verified that CPT1A was more highly expressed in colon cancer tissues than in noncancerous tissues. Silencing CPT1A by siRNA or etomoxir, a specific small‐molecule inhibitor of CPT1A, could reverse the sensitivity of drug‐resistant colon cancer cells to oxaliplatin. Subsequently, the combination of oxaliplatin with CPT1A inhibition promoted apoptosis and inhibited proliferation. In addition, exosomes were generated with the iRGD peptide on the surface, which showed highly efficient targeting compared with control exosomes in vivo. Furthermore, we loaded and therapeutically applied iRGD‐modified exosomes with siCPT1A to specifically deliver siCPT1A into tumours to suppress FAO. As a consequence, iRGD‐modified exosomes showed the significant inhibition of CPT1A in tumour tissues and exhibited the ability to reverse oxaliplatin resistance and inhibit tumour growth by inhibiting FAO with high safety in vivo.Dan LinHaiyang ZhangRui LiuTing DengTao NingMing BaiYuchong YangKegan ZhuJunyi WangJingjing DuanShaohua GeBei SunGuoguang YingYi BaWileyarticlechemoresistancecolon cancerexosomesFAOiRGDoxaliplatinNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Oncology, Vol 15, Iss 12, Pp 3430-3446 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chemoresistance colon cancer exosomes FAO iRGD oxaliplatin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	chemoresistance colon cancer exosomes FAO iRGD oxaliplatin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Dan Lin Haiyang Zhang Rui Liu Ting Deng Tao Ning Ming Bai Yuchong Yang Kegan Zhu Junyi Wang Jingjing Duan Shaohua Ge Bei Sun Guoguang Ying Yi Ba iRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation
description	Fatty acid oxidation (FAO) plays a vital role in drug resistance in cancer cells. Carnitine palmitoyltransferase 1A (CPT1A), a key enzyme of FAO, is widely recognized as an emerging therapeutic target. Here, we confirmed that CPT1A was heterogeneously expressed in colon cancer cells, with a high expression in oxaliplatin‐resistant cells but low expression in oxaliplatin‐sensitive cells, and expression could be increased by oxaliplatin stimulation. In addition, we verified that CPT1A was more highly expressed in colon cancer tissues than in noncancerous tissues. Silencing CPT1A by siRNA or etomoxir, a specific small‐molecule inhibitor of CPT1A, could reverse the sensitivity of drug‐resistant colon cancer cells to oxaliplatin. Subsequently, the combination of oxaliplatin with CPT1A inhibition promoted apoptosis and inhibited proliferation. In addition, exosomes were generated with the iRGD peptide on the surface, which showed highly efficient targeting compared with control exosomes in vivo. Furthermore, we loaded and therapeutically applied iRGD‐modified exosomes with siCPT1A to specifically deliver siCPT1A into tumours to suppress FAO. As a consequence, iRGD‐modified exosomes showed the significant inhibition of CPT1A in tumour tissues and exhibited the ability to reverse oxaliplatin resistance and inhibit tumour growth by inhibiting FAO with high safety in vivo.
format	article
author	Dan Lin Haiyang Zhang Rui Liu Ting Deng Tao Ning Ming Bai Yuchong Yang Kegan Zhu Junyi Wang Jingjing Duan Shaohua Ge Bei Sun Guoguang Ying Yi Ba
author_facet	Dan Lin Haiyang Zhang Rui Liu Ting Deng Tao Ning Ming Bai Yuchong Yang Kegan Zhu Junyi Wang Jingjing Duan Shaohua Ge Bei Sun Guoguang Ying Yi Ba
author_sort	Dan Lin
title	iRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation
title_short	iRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation
title_full	iRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation
title_fullStr	iRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation
title_full_unstemmed	iRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation
title_sort	irgd‐modified exosomes effectively deliver cpt1a sirna to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/0c60783763d74dd89591e440358a62b7
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iRGD‐modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation

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