Targeted delivery of FAK siRNA by engineered exosomes to reverse cetuximab resistance via activating paraptosis in colon cancer.

Autor: Geng Y; Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China., Xia W; Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China., Zheng X; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.; Tumor Biological Diagnosis and Treatment Center, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.; Institute of Cell Therapy, Soochow University, Changzhou, 213003, China., Chen L; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.; Tumor Biological Diagnosis and Treatment Center, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.; Institute of Cell Therapy, Soochow University, Changzhou, 213003, China., Zhou Y; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.; Tumor Biological Diagnosis and Treatment Center, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.; Institute of Cell Therapy, Soochow University, Changzhou, 213003, China., Feng J; Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China., Yuan Y; Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China., Zhang M; Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China., Lu J; Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China., Wei S; Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China., Hu W; Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China. huwenwei@suda.edu.cn.; Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China. huwenwei@suda.edu.cn.
Jazyk: angličtina
Zdroj: Apoptosis : an international journal on programmed cell death [Apoptosis] 2024 Jul 03. Date of Electronic Publication: 2024 Jul 03.
DOI: 10.1007/s10495-024-01986-x
Abstrakt: Background: Cetuximab is extensively used in the treatment of metastatic colorectal cancer (mCRC). However, resistance poses a significant challenge to successful therapy. Recently, paraptosis, a non-classical programmed cell death, has garnered increased attention for its potential application value in antitumor treatments. We aimed to identify the essential pathways and signaling molecules involved in paraptosis inhibition and select them as therapeutic targets in cetuximab resistance. Additionally, engineered exosome technology is used as a drug delivery system with both targeted and effector properties.
Results: By comparing the differential expression of paraptosis-related genes between drug-resistant colon cancer cells and sensitive cells, it was observed that the paraptosis level induced by cetuximab was significantly downregulated in drug-resistant cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified the focal adhesion kinase (FAK) signaling pathway as a key pathway involved in the suppression of paraptosis. The biological function of FAK in cetuximab-resistant cells was investigated through cell morphology observation, CCK-8 assay, colony formation assay, RT-qPCR, Western Blot, and loss-of-function experiments. The results showed that the FAK signaling pathway was significantly upregulated in cetuximab-resistant colon cancer cells, and siRNA interference targeting FAK could notably inhibit cell proliferation while upregulating the paraptosis level. Based on this, engineered colon cancer cells targeted and FAK siRNA loaded exosomes (CT-Exo-siFAK1) were constructed. In vitro experiments, CT-Exo-siFAK1 could effectively activate paraptosis and inhibit the proliferation of drug-resistant colon cancer cells. In vivo experiments also confirmed that CT-Exo-siFAK1 significantly suppressed tumor growth and metastasis while upregulating the paraptosis level.
Conclusion: This study suggests that FAK signaling pathway-mediated inhibition of paraptosis levels is crucial in the sensitivity of cetuximab targeted therapy in colon cancer, and the use of engineered exosomes to deliver FAK siRNA may be an effective strategy to reverse cetuximab resistance.
(© 2024. The Author(s).)
Databáze: MEDLINE
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