LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathway
Abstract Autophagy is one of the underlying causes of resistance to many antitumor drugs, including cisplatin (DDP). The low‐density lipoprotein receptor (LDLR) is a regulator of ovarian cancer (OC) progression. However, whether LDLR regulates DDP resistance in OC via autophagy‐related pathways rema...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-08-01
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| Series: | Kaohsiung Journal of Medical Sciences |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/kjm2.12696 |
| _version_ | 1797744358515015680 |
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| author | Lei Liu Yu‐Hui Sun Ran An Rong‐Jie Cheng Nan Li Jian‐Hua Zheng |
| author_facet | Lei Liu Yu‐Hui Sun Ran An Rong‐Jie Cheng Nan Li Jian‐Hua Zheng |
| author_sort | Lei Liu |
| collection | DOAJ |
| description | Abstract Autophagy is one of the underlying causes of resistance to many antitumor drugs, including cisplatin (DDP). The low‐density lipoprotein receptor (LDLR) is a regulator of ovarian cancer (OC) progression. However, whether LDLR regulates DDP resistance in OC via autophagy‐related pathways remains unclear. LDLR expression was measured by quantitative real‐time PCR, western blot (WB) and IHC staining. A Cell Counting Kit 8 assay was employed to evaluate DDP resistance and cell viability, and flow cytometry was used to assess apoptosis. WB analysis was employed to evaluate the expression of autophagy‐related proteins and PI3K/AKT/mTOR signaling pathway proteins. The autophagolysosomes and the fluorescence intensity of LC3 were observed by transmission electron microscopy and immunofluorescence staining, respectively. A xenograft tumor model was established to explore the role of LDLR in vivo. LDLR was highly expressed in OC cells, which was correlated with disease progression. In DDP‐resistant OC cells, high LDLR expression was related to DDP resistance and autophagy. Downregulation of LDLR repressed autophagy and growth in DDP‐resistant OC cell lines by activating the PI3K/AKT/mTOR pathway, and these effects were eliminated by an mTOR inhibitor. In addition, LDLR knockdown also reduced OC tumor growth by suppressing autophagy associated with the PI3K/AKT/mTOR pathway. LDLR promoted autophagy‐mediated DDP resistance in OC associated with the PI3K/AKT/mTOR pathway, indicating that LDLR might be a new target to prevent DDP resistance in OC patients. |
| first_indexed | 2024-03-12T15:08:37Z |
| format | Article |
| id | doaj.art-cf77ee522a274176b828dc3593f6241d |
| institution | Directory Open Access Journal |
| issn | 1607-551X 2410-8650 |
| language | English |
| last_indexed | 2024-03-12T15:08:37Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Kaohsiung Journal of Medical Sciences |
| spelling | doaj.art-cf77ee522a274176b828dc3593f6241d2023-08-12T03:36:47ZengWileyKaohsiung Journal of Medical Sciences1607-551X2410-86502023-08-0139877978810.1002/kjm2.12696LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathwayLei Liu0Yu‐Hui Sun1Ran An2Rong‐Jie Cheng3Nan Li4Jian‐Hua Zheng5Department of Obstetrics and Gynecology The Fourth Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province People's Republic of ChinaDepartment of Obstetrics and Gynecology The First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province People's Republic of ChinaDepartment of Obstetrics and Gynecology The Fourth Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province People's Republic of ChinaDepartment of Obstetrics and Gynecology The Fourth Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province People's Republic of ChinaDepartment of Pathology The Fourth Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province People's Republic of ChinaDepartment of Obstetrics and Gynecology The First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang Province People's Republic of ChinaAbstract Autophagy is one of the underlying causes of resistance to many antitumor drugs, including cisplatin (DDP). The low‐density lipoprotein receptor (LDLR) is a regulator of ovarian cancer (OC) progression. However, whether LDLR regulates DDP resistance in OC via autophagy‐related pathways remains unclear. LDLR expression was measured by quantitative real‐time PCR, western blot (WB) and IHC staining. A Cell Counting Kit 8 assay was employed to evaluate DDP resistance and cell viability, and flow cytometry was used to assess apoptosis. WB analysis was employed to evaluate the expression of autophagy‐related proteins and PI3K/AKT/mTOR signaling pathway proteins. The autophagolysosomes and the fluorescence intensity of LC3 were observed by transmission electron microscopy and immunofluorescence staining, respectively. A xenograft tumor model was established to explore the role of LDLR in vivo. LDLR was highly expressed in OC cells, which was correlated with disease progression. In DDP‐resistant OC cells, high LDLR expression was related to DDP resistance and autophagy. Downregulation of LDLR repressed autophagy and growth in DDP‐resistant OC cell lines by activating the PI3K/AKT/mTOR pathway, and these effects were eliminated by an mTOR inhibitor. In addition, LDLR knockdown also reduced OC tumor growth by suppressing autophagy associated with the PI3K/AKT/mTOR pathway. LDLR promoted autophagy‐mediated DDP resistance in OC associated with the PI3K/AKT/mTOR pathway, indicating that LDLR might be a new target to prevent DDP resistance in OC patients.https://doi.org/10.1002/kjm2.12696autophagycisplatin resistancelow‐density lipoprotein receptorovarian cancer |
| spellingShingle | Lei Liu Yu‐Hui Sun Ran An Rong‐Jie Cheng Nan Li Jian‐Hua Zheng LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathway Kaohsiung Journal of Medical Sciences autophagy cisplatin resistance low‐density lipoprotein receptor ovarian cancer |
| title | LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathway |
| title_full | LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathway |
| title_fullStr | LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathway |
| title_full_unstemmed | LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathway |
| title_short | LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathway |
| title_sort | ldlr promotes autophagy mediated cisplatin resistance in ovarian cancer associated with the pi3k akt mtor signaling pathway |
| topic | autophagy cisplatin resistance low‐density lipoprotein receptor ovarian cancer |
| url | https://doi.org/10.1002/kjm2.12696 |
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