Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer
Abstract Annexin A10 (ANXA10) belongs to a family of membrane-bound calcium-dependent phospholipid-binding proteins, but its precise function remains unclear. Further research is required to understand its role in sessile serrated lesions (SSL) and colorectal cancer (CRC). We conducted transcriptome...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06114-2 |
| _version_ | 1797653532061466624 |
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| author | Xinyuan Wang Yujie Zhou Lijun Ning Jinnan Chen Huimin Chen Xiaobo Li |
| author_facet | Xinyuan Wang Yujie Zhou Lijun Ning Jinnan Chen Huimin Chen Xiaobo Li |
| author_sort | Xinyuan Wang |
| collection | DOAJ |
| description | Abstract Annexin A10 (ANXA10) belongs to a family of membrane-bound calcium-dependent phospholipid-binding proteins, but its precise function remains unclear. Further research is required to understand its role in sessile serrated lesions (SSL) and colorectal cancer (CRC). We conducted transcriptome sequencing on pairs of SSL and corresponding normal control (NC) samples. Bioinformatic methods were utilized to assess ANXA10 expression in CRC. We knocked down and overexpressed ANXA10 in CRC cells to examine its effects on cell malignant ability. The effect of ANXA10 on lung metastasis of xenograft tumor cells in nude mice was also assessed. Furthermore, we used quantitative polymerase chain reaction, western blotting, and flow cytometry for reactive oxygen species (ROS), lipid ROS, and intracellular Fe2+ to measure ferroptosis. Immunoblotting and Immunofluorescence staining were used to detect autophagy. We found that ANXA10 was significantly overexpressed in SSL compared to NC. ANXA10 was also highly expressed in BRAF mutant CRCs and was associated with poor prognosis. ANXA10 knockdown reduced the survival, proliferation, and migration ability of CRC cells. Knockdown of ANXA10 inhibited lung metastasis of CRC cells in mice. ANXA10 knockdown increased transferrin receptor (TFRC) protein levels and led to downregulation of GSH/GSSG, increased Fe2+, MDA concentration, and ROS and lipid ROS in cells. Knockdown of ANXA10 inhibited TFRC degradation and was accompanied by an accumulation of autophagic flux and an increase in SQSTM1. Finally, Fer-1 rescued the migration and viability of ANXA10 knockdown cell lines. In brief, the knockdown of ANXA10 induces cellular ferroptosis by inhibiting autophagy-mediated TFRC degradation, thereby inhibiting CRC progression. This study reveals the mechanism of ANXA10 in ferroptosis, suggesting that it may serve as a potential therapeutic target for CRC of the serrated pathway. |
| first_indexed | 2024-03-11T16:45:55Z |
| format | Article |
| id | doaj.art-174293827e0d4131be361339a8fe5107 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-11T16:45:55Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-174293827e0d4131be361339a8fe51072023-10-22T11:29:12ZengNature Publishing GroupCell Death and Disease2041-48892023-09-0114911310.1038/s41419-023-06114-2Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancerXinyuan Wang0Yujie Zhou1Lijun Ning2Jinnan Chen3Huimin Chen4Xiaobo Li5Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDivision of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityAbstract Annexin A10 (ANXA10) belongs to a family of membrane-bound calcium-dependent phospholipid-binding proteins, but its precise function remains unclear. Further research is required to understand its role in sessile serrated lesions (SSL) and colorectal cancer (CRC). We conducted transcriptome sequencing on pairs of SSL and corresponding normal control (NC) samples. Bioinformatic methods were utilized to assess ANXA10 expression in CRC. We knocked down and overexpressed ANXA10 in CRC cells to examine its effects on cell malignant ability. The effect of ANXA10 on lung metastasis of xenograft tumor cells in nude mice was also assessed. Furthermore, we used quantitative polymerase chain reaction, western blotting, and flow cytometry for reactive oxygen species (ROS), lipid ROS, and intracellular Fe2+ to measure ferroptosis. Immunoblotting and Immunofluorescence staining were used to detect autophagy. We found that ANXA10 was significantly overexpressed in SSL compared to NC. ANXA10 was also highly expressed in BRAF mutant CRCs and was associated with poor prognosis. ANXA10 knockdown reduced the survival, proliferation, and migration ability of CRC cells. Knockdown of ANXA10 inhibited lung metastasis of CRC cells in mice. ANXA10 knockdown increased transferrin receptor (TFRC) protein levels and led to downregulation of GSH/GSSG, increased Fe2+, MDA concentration, and ROS and lipid ROS in cells. Knockdown of ANXA10 inhibited TFRC degradation and was accompanied by an accumulation of autophagic flux and an increase in SQSTM1. Finally, Fer-1 rescued the migration and viability of ANXA10 knockdown cell lines. In brief, the knockdown of ANXA10 induces cellular ferroptosis by inhibiting autophagy-mediated TFRC degradation, thereby inhibiting CRC progression. This study reveals the mechanism of ANXA10 in ferroptosis, suggesting that it may serve as a potential therapeutic target for CRC of the serrated pathway.https://doi.org/10.1038/s41419-023-06114-2 |
| spellingShingle | Xinyuan Wang Yujie Zhou Lijun Ning Jinnan Chen Huimin Chen Xiaobo Li Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer Cell Death and Disease |
| title | Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer |
| title_full | Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer |
| title_fullStr | Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer |
| title_full_unstemmed | Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer |
| title_short | Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer |
| title_sort | knockdown of anxa10 induces ferroptosis by inhibiting autophagy mediated tfrc degradation in colorectal cancer |
| url | https://doi.org/10.1038/s41419-023-06114-2 |
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