iRGD-modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation.
iRGD-modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation.
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iRGD 修饰的外泌体有效地将 CPT1A siRNA 递送至结肠癌细胞，通过调节脂肪酸氧化来逆转奥沙利铂耐药性。
DOI：
10.1002/1878-0261.13052
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发表时间：
2021-12
影响因子：
6.6
通讯作者：
Ba Y
中科院分区：
文献类型：
--
作者：
Lin D;Zhang H;Liu R;Deng T;Ning T;Bai M;Yang Y;Zhu K;Wang J;Duan J;Ge S;Sun B;Ying G;Ba Y
脂肪酸氧化（FAO）在癌细胞的耐药性中起着至关重要的作用。肉毒碱棕榈酰转移酶1A（Carnitine palmitoyltransferase 1A，CPT 1A）是FAO的关键酶，是公认的治疗靶点。在这里，我们证实了CPT 1A在结肠癌细胞中的异质性表达，在奥沙利铂耐药细胞中高表达，但在奥沙利铂敏感细胞中低表达，并且表达可以通过奥沙利铂刺激来增加。此外，我们证实了CPT 1A在结肠癌组织中比在非癌组织中更高表达。通过siRNA或CPT 1A的特异性小分子抑制剂etomoxir沉默CPT 1A，可以逆转耐药结肠癌细胞对奥沙利铂的敏感性。随后，奥沙利铂与CPT 1A抑制剂的组合促进细胞凋亡并抑制增殖。此外，在表面上产生具有iRGD肽的外泌体，与体内对照外泌体相比，其显示出高效的靶向。此外，我们用siCPT 1A装载并治疗性地应用iRGD修饰的外泌体，以特异性地将siCPT 1A递送到肿瘤中以抑制FAO。因此，iRGD修饰的外泌体显示出对肿瘤组织中CPT 1A的显著抑制，并显示出逆转奥沙利铂耐药性和通过抑制FAO抑制肿瘤生长的能力，体内安全性高。脂肪酸氧化（FAO）在癌细胞的耐药性中起着至关重要的作用。肉毒碱棕榈酰转移酶1A（Carnitine palmitoyltransferase 1A，CPT 1A）在结肠癌组织中有高表达。在这里，我们证明了iRGD-外泌体-siCPT 1A沉默CPT 1A有效地抑制了FAO，抑制了肿瘤发生并逆转了结肠癌中的奥沙利铂耐药性。总之，iRGD-外泌体-siCPT 1A介导的FAO沉默可能是治疗奥沙利铂耐药结肠癌患者的有效方法，并可能推动iRGD工程外泌体在癌症治疗中用于siRNA递送的临床应用。
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. Fatty acid oxidation (FAO) plays a vital role in drug resistance in cancer cells. High expression of Carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in FAO, was observed in colon cancer tissues. Here, we demonstrated that silencing of CPT1A by iRGD‐exosome‐siCPT1A efficiently suppressed FAO, inhibited tumorigenesis and reversed oxaliplatin resistance in colon cancer. Altogether, iRGD‐exosome‐siCPT1A mediated silencing of FAO may serve as an effective approach to treat oxaliplatin‐resistant patient with colon cancer and may propel the clinical application of iRGD‐engineered exosomes for siRNA delivery in cancer treatment.
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影响因子：
46.9
作者：
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通讯作者：
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