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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Autores principales:	Li-Wei Sun, Shao-Hsuan Kao, Shun-Fa Yang, Shang-Wun Jhang, Yi-Chen Lin, Chien-Min Chen, Yi-Hsien Hsieh
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	corosolic acid glioblastoma cell invasiveness AXL CHIP GAS6 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2d2790148b164bb9bcae0fc1fdb7e53d
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spelling	oai:doaj.org-article:2d2790148b164bb9bcae0fc1fdb7e53d2021-11-25T17:08:54ZCorosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis10.3390/cells101129192073-4409https://doaj.org/article/2d2790148b164bb9bcae0fc1fdb7e53d2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2919https://doaj.org/toc/2073-4409Corosolic 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.Li-Wei SunShao-Hsuan KaoShun-Fa YangShang-Wun JhangYi-Chen LinChien-Min ChenYi-Hsien HsiehMDPI AGarticlecorosolic acidglioblastoma cellinvasivenessAXLCHIPGAS6Biology (General)QH301-705.5ENCells, Vol 10, Iss 2919, p 2919 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	corosolic acid glioblastoma cell invasiveness AXL CHIP GAS6 Biology (General) QH301-705.5
spellingShingle	corosolic acid glioblastoma cell invasiveness AXL CHIP GAS6 Biology (General) QH301-705.5 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
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.
format	article
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
title	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_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_sort	corosolic acid attenuates the invasiveness of glioblastoma cells by promoting chip-mediated axl degradation and inhibiting gas6/axl/jak axis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2d2790148b164bb9bcae0fc1fdb7e53d
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Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis

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