Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)‐Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib
Abstract Tyrosine kinase inhibitors represented by sorafenib are the first‐line treatment for hepatocellular carcinoma (HCC), but the low response rate of HCC patient has become a clinical pain‐point. Emerging evidences have revealed that metabolic reprogramming plays an important role in regulating...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-07-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202207118 |
| _version_ | 1797786154119987200 |
|---|---|
| author | Senlin Li Lei Xu Guo Wu Ziqi Huang Linzhuo Huang Fengqian Zhang Chunfang Wei Qian Shen Rong Li Lei Zhang Xiaoding Xu |
| author_facet | Senlin Li Lei Xu Guo Wu Ziqi Huang Linzhuo Huang Fengqian Zhang Chunfang Wei Qian Shen Rong Li Lei Zhang Xiaoding Xu |
| author_sort | Senlin Li |
| collection | DOAJ |
| description | Abstract Tyrosine kinase inhibitors represented by sorafenib are the first‐line treatment for hepatocellular carcinoma (HCC), but the low response rate of HCC patient has become a clinical pain‐point. Emerging evidences have revealed that metabolic reprogramming plays an important role in regulating the sensitivity of tumor cells to various chemotherapeutics including sorafenib. However, the underlying mechanisms are very complex and are not fully elucidated. By comparing the transcriptome sequencing data of sorafenib‐sensitive and ‐insensitive HCC patients, it is revealed that cofilin 1 (CFL1) is highly expressed in the tumor tissues of sorafenib‐insensitive HCC patients and closely correlated with their poor prognosis. Mechanically, CFL1 can promote phosphoglycerate dehydrogenase transcription and enhance serine synthesis and metabolism to accelerate the production of antioxidants for scavenging the excessive reactive oxygen species induced by sorafenib, thereby impairing the sorafenib sensitivity of HCC. To translate this finding and consider the severe side effects of sorafenib, a reduction‐responsive nanoplatform for systemic co‐delivery of CFL1 siRNA (siCFL1) and sorafenib is further developed, and its high efficacy in inhibiting HCC tumor growth without apparent toxicity is demonstrated. These results indicate that nanoparticles‐mediated co‐delivery of siCFL1 and sorafenib can be a new strategy for the treatment of advanced HCC. |
| first_indexed | 2024-03-13T01:04:54Z |
| format | Article |
| id | doaj.art-754ae8eecf674b3ab61bdc022e83ceb3 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-13T01:04:54Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-754ae8eecf674b3ab61bdc022e83ceb32023-07-06T07:39:03ZengWileyAdvanced Science2198-38442023-07-011019n/an/a10.1002/advs.202207118Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)‐Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to SorafenibSenlin Li0Lei Xu1Guo Wu2Ziqi Huang3Linzhuo Huang4Fengqian Zhang5Chunfang Wei6Qian Shen7Rong Li8Lei Zhang9Xiaoding Xu10Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaThe Second Affiliated Hospital Hengyang Medical School University of South China Hengyang 421001 P. R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong‐Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou 510120 P. R. ChinaAbstract Tyrosine kinase inhibitors represented by sorafenib are the first‐line treatment for hepatocellular carcinoma (HCC), but the low response rate of HCC patient has become a clinical pain‐point. Emerging evidences have revealed that metabolic reprogramming plays an important role in regulating the sensitivity of tumor cells to various chemotherapeutics including sorafenib. However, the underlying mechanisms are very complex and are not fully elucidated. By comparing the transcriptome sequencing data of sorafenib‐sensitive and ‐insensitive HCC patients, it is revealed that cofilin 1 (CFL1) is highly expressed in the tumor tissues of sorafenib‐insensitive HCC patients and closely correlated with their poor prognosis. Mechanically, CFL1 can promote phosphoglycerate dehydrogenase transcription and enhance serine synthesis and metabolism to accelerate the production of antioxidants for scavenging the excessive reactive oxygen species induced by sorafenib, thereby impairing the sorafenib sensitivity of HCC. To translate this finding and consider the severe side effects of sorafenib, a reduction‐responsive nanoplatform for systemic co‐delivery of CFL1 siRNA (siCFL1) and sorafenib is further developed, and its high efficacy in inhibiting HCC tumor growth without apparent toxicity is demonstrated. These results indicate that nanoparticles‐mediated co‐delivery of siCFL1 and sorafenib can be a new strategy for the treatment of advanced HCC.https://doi.org/10.1002/advs.202207118cofilin 1hepatocellular carcinomananoparticlesserine synthesis and metabolismsorafenib sensitivity |
| spellingShingle | Senlin Li Lei Xu Guo Wu Ziqi Huang Linzhuo Huang Fengqian Zhang Chunfang Wei Qian Shen Rong Li Lei Zhang Xiaoding Xu Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)‐Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib Advanced Science cofilin 1 hepatocellular carcinoma nanoparticles serine synthesis and metabolism sorafenib sensitivity |
| title | Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)‐Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib |
| title_full | Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)‐Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib |
| title_fullStr | Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)‐Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib |
| title_full_unstemmed | Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)‐Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib |
| title_short | Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)‐Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib |
| title_sort | remodeling serine synthesis and metabolism via nanoparticles nps mediated cfl1 silencing to enhance the sensitivity of hepatocellular carcinoma to sorafenib |
| topic | cofilin 1 hepatocellular carcinoma nanoparticles serine synthesis and metabolism sorafenib sensitivity |
| url | https://doi.org/10.1002/advs.202207118 |
| work_keys_str_mv | AT senlinli remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT leixu remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT guowu remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT ziqihuang remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT linzhuohuang remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT fengqianzhang remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT chunfangwei remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT qianshen remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT rongli remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT leizhang remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib AT xiaodingxu remodelingserinesynthesisandmetabolismviananoparticlesnpsmediatedcfl1silencingtoenhancethesensitivityofhepatocellularcarcinomatosorafenib |