Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis
Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-cancer activities. Glioblastoma (GBM) is a malignant brain tumor and whether CA exerts anti-cancer activity on GBM remains unclear. This study was aimed to explore the anticancer activity and its underlyi...
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MDPI AG
2021-10-01
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| author | Li-Wei Sun Shao-Hsuan Kao Shun-Fa Yang Shang-Wun Jhang Yi-Chen Lin Chien-Min Chen Yi-Hsien Hsieh |
| author_facet | Li-Wei Sun Shao-Hsuan Kao Shun-Fa Yang Shang-Wun Jhang Yi-Chen Lin Chien-Min Chen Yi-Hsien Hsieh |
| author_sort | Li-Wei Sun |
| collection | DOAJ |
| description | Corosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-cancer activities. Glioblastoma (GBM) is a malignant brain tumor and whether CA exerts anti-cancer activity on GBM remains unclear. This study was aimed to explore the anticancer activity and its underlying mechanism of CA in GBM cells. Our findings showed that CA ≤ 20 μM did not affect cell viability and cell proliferative rate of normal astrocyte and four GBM cells. Notably, 10 or 20 μM CA significantly inhibited cell migration and invasion of three GBM cells, decreased the protein level of F-actin and disrupted F-actin polymerization in these GBM cells. Further investigation revealed that CA decreased AXL level by promoting ubiquitin-mediated proteasome degradation and upregulating the carboxyl terminus of Hsc70-interacting protein (CHIP), an inducer of AXL polyubiquitination. CHIP knock-down restored the CA-reduced AXL and invasiveness of GBM cells. Additionally, we observed that CA-reduced Growth arrest-specific protein 6 (GAS6) and inhibited JAK2/MEK/ERK activation, and GAS6 pre-treatment restored attenuated JAK2/MEK/ERK activation and invasiveness of GBM cells. Furthermore, molecular docking analysis revealed that CA might bind to GAS6 and AXL. These findings collectively indicate that CA attenuates the invasiveness of GBM cells, attributing to CHIP upregulation and binding to GAS6 and AXL and subsequently promoting AXL degradation and downregulating GAS6-mediated JAK2/MEK/ERK cascade. Conclusively, this suggests that CA has potential anti-metastatic activity on GBM cells by targeting the CHIP/GAS6/AXL axis. |
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| last_indexed | 2024-03-10T05:37:07Z |
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| spelling | doaj.art-2d2790148b164bb9bcae0fc1fdb7e53d2023-11-22T22:48:41ZengMDPI AGCells2073-44092021-10-011011291910.3390/cells10112919Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK AxisLi-Wei Sun0Shao-Hsuan Kao1Shun-Fa Yang2Shang-Wun Jhang3Yi-Chen Lin4Chien-Min Chen5Yi-Hsien Hsieh6Institute of Medicine, Chung Shan Medical University, Taichung 40201, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 40201, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 40201, TaiwanDivision of Neurosurgery, Department of Surgery, Changhua Christian Hospital, Changhua 50006, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 40201, TaiwanDivision of Neurosurgery, Department of Surgery, Changhua Christian Hospital, Changhua 50006, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 40201, TaiwanCorosolic acid (CA), a bioactive compound obtained from Actinidia chinensis, has potential anti-cancer activities. Glioblastoma (GBM) is a malignant brain tumor and whether CA exerts anti-cancer activity on GBM remains unclear. This study was aimed to explore the anticancer activity and its underlying mechanism of CA in GBM cells. Our findings showed that CA ≤ 20 μM did not affect cell viability and cell proliferative rate of normal astrocyte and four GBM cells. Notably, 10 or 20 μM CA significantly inhibited cell migration and invasion of three GBM cells, decreased the protein level of F-actin and disrupted F-actin polymerization in these GBM cells. Further investigation revealed that CA decreased AXL level by promoting ubiquitin-mediated proteasome degradation and upregulating the carboxyl terminus of Hsc70-interacting protein (CHIP), an inducer of AXL polyubiquitination. CHIP knock-down restored the CA-reduced AXL and invasiveness of GBM cells. Additionally, we observed that CA-reduced Growth arrest-specific protein 6 (GAS6) and inhibited JAK2/MEK/ERK activation, and GAS6 pre-treatment restored attenuated JAK2/MEK/ERK activation and invasiveness of GBM cells. Furthermore, molecular docking analysis revealed that CA might bind to GAS6 and AXL. These findings collectively indicate that CA attenuates the invasiveness of GBM cells, attributing to CHIP upregulation and binding to GAS6 and AXL and subsequently promoting AXL degradation and downregulating GAS6-mediated JAK2/MEK/ERK cascade. Conclusively, this suggests that CA has potential anti-metastatic activity on GBM cells by targeting the CHIP/GAS6/AXL axis.https://www.mdpi.com/2073-4409/10/11/2919corosolic acidglioblastoma cellinvasivenessAXLCHIPGAS6 |
| spellingShingle | Li-Wei Sun Shao-Hsuan Kao Shun-Fa Yang Shang-Wun Jhang Yi-Chen Lin Chien-Min Chen Yi-Hsien Hsieh Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis Cells corosolic acid glioblastoma cell invasiveness AXL CHIP GAS6 |
| title | Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis |
| title_full | Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis |
| title_fullStr | Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis |
| title_full_unstemmed | Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis |
| title_short | Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis |
| title_sort | corosolic acid attenuates the invasiveness of glioblastoma cells by promoting chip mediated axl degradation and inhibiting gas6 axl jak axis |
| topic | corosolic acid glioblastoma cell invasiveness AXL CHIP GAS6 |
| url | https://www.mdpi.com/2073-4409/10/11/2919 |
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