Silibinin Induced Human Glioblastoma Cell Apoptosis Concomitant with Autophagy through Simultaneous Inhibition of mTOR and YAP.

Zhuan-Li Bai,Mao-Guo Shu,Juan Ren,Vincent Tay,Shu-Zhong Guo

doi:10.1155/2018/6165192

Abstract

Silibinin, also known as silybin, is the major flavonolignan isolated from Silybum marianum. Although previous reports demonstrated that silibinin exhibits significant tumor suppressor activities in various cancers by promoting cell apoptosis, it was also shown to trigger autophagy to counteract apoptosis induced by exogenous stresses in several types of cells. However, there is no report to address the role of silibinin induced autophagy in human A172 and SR glioblastoma cells. Our study showed that silibinin treatment not only inhibited the metabolic activities of glioblastoma cells but also promoted their apoptosis through the regulation of caspase 3 and PARP-1 in concentration- and time-dependent manners. Meanwhile, silibinin induced autophagy through upregulation of microtubule-associated protein a light chain 3- (LC3-) II. And autophagy inhibition with chloroquine, a lysosomotropic agent, significantly enhanced silibinin induced glioblastoma cell apoptosis. Moreover, silibinin dose-dependently downregulated the phosphorylation levels of mTOR at Ser-2448, p70S6K at Thr-389, and 4E-BP1 at Thr-37/46. Furthermore, the expression of YAP, the downstream effector of Hippo signal pathway, was also suppressed by silibinin. These results suggested that silibinin induced glioblastoma cell apoptosis concomitant with autophagy which might be due to simultaneous inhibition of mTOR and YAP and silibinin induced autophagy exerted a protective role against cell apoptosis in both A172 and SR cells.

Highlights

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor, which constitutes 16% of all primary central nervous system neoplasms
Our results showed that silibinin treatment led to the cleavage of caspase 3 and poly (ADO-ribose) polymerase 1 (PARP-1) in both SR and A172 cells in a concentrationdependent manner (Figure 2(b)), indicating that silibinin induces glioblastoma cell apoptosis via a caspase-dependent PARP-1 cleavage, which has been widely considered to be a hallmark of apoptosis
In view of the fact that autophagy has been considered as a double-edged sword and functions as both tumor suppressor and tumor promoter, we further evaluated the effect of autophagy inhibition on silibinin induced glioblastoma cell apoptosis

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor, which constitutes 16% of all primary central nervous system neoplasms. Silibinin was reported to have significant tumor suppressor functions in various cancers, including cancers of the breast, prostate, lung, bladder, colon, skin, and kidney [11,12,13,14,15,16,17,18,19,20]. It can significantly suppress the invasion and metastasis of cancer cells [21, 22]. Silibinin enhances the sensitivity of various human glioblastoma cell lines to several chemotherapeutic drugs including temozolomide, etoposide, O

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