Corosolic Acid Attenuates the Invasiveness of Glioblastoma Cells by Promoting CHIP-Mediated AXL Degradation and Inhibiting GAS6/AXL/JAK Axis.

Li-Wei Sun,Chien-Min Chen,Yi-Chen Lin,Shun-Fa Yang,Yi-Hsien Hsieh,Shang-Wun Jhang,Shao-Hsuan Kao

doi:10.3390/cells10112919

Abstract

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.

Highlights

Due to the introduction of alkylating agents, such as temozolomide and adjuvant therapy combined with radiotherapy and temozolomide, the median survival time of patients with GBM increased from 12.1 months to 14.6 months. [4,5]
After 24- or 48-h treatments, cell viability was remarkably reduced by Corosolic acid (CA) at 25 and 30 μM (p < 0.05), but unaffected by CA at 10, 15 and 20 μM compared with the control (Figure 1B,C)
An exception showed that 20 μM CA treatment for 48 h could decrease the cell viability of CTX-TNA2 cells to 84.7% ± 5.3% of control (p < 0.05) were detected by MTT assay

Summary

Introduction

Glioma is the most common form of brain tumor, and glioblastoma (GBM) is the most malignant glioma, accounting for 3–4% of all cancer-associated deaths [1]. The five-year survival rate for patients with GBM is approximately 4–5%, indicating that the prognosis of GBM is poor [2]. The standard treatment for GBM includes resection with concurrent radiotherapy and chemotherapy. The current standard treatment did not significantly increase the survival rate of patients with GBM compared with those with glioma and other subtypes [3]. Due to the introduction of alkylating agents, such as temozolomide and adjuvant therapy combined with radiotherapy and temozolomide, the median survival time of patients with GBM increased from 12.1 months to 14.6 months. Due to the introduction of alkylating agents, such as temozolomide and adjuvant therapy combined with radiotherapy and temozolomide, the median survival time of patients with GBM increased from 12.1 months to 14.6 months. [4,5]

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