Silibinin inhibits epithelial‑mesenchymal transition of renal cell carcinoma through autophagy‑dependent Wnt/β‑catenin signaling

Abstract

Silibinin is a flavonoid extracted from milk thistle seeds which has been widely used as a hepatoprotective and antioxidant agent. Recently, accumulating evidence has demonstrated the anti-cancer effects of silibinin in various cancer models. It was previously reported that silibinin induced apoptosis and decreased metastasis by activating autophagy in renal cell carcinoma (RCC). However, the underlying molecular mechanisms by which silibinin regulates autophagy remain largely unknown. The aim of the present study was to investigate the effects of silibinin on RCC metastasis in vitro and in vivo, with a focus on autophagy-dependent Wnt/β-catenin signaling. Human RCC 786-O and ACHN cell lines were used as the model system in vitro and RCC xenografts of nude mice were used for in vivo studies. Silibinin inhibited metastasis and epithelial-mesenchymal transition (EMT) of RCC in vitro and in vivo, by regulating the Wnt/β-catenin signaling pathway. Furthermore, silibinin inhibited the Wnt/β-catenin signaling pathway in an autophagy-dependent manner. Autophagic degradation of β-catenin induced by silibinin was associated with the anti-metastatic effects of silibinin against RCC. These findings identify a novel mechanism by which silibinin inhibits EMT and metastasis of RCC, highlighting a potential novel strategy for treating metastatic RCC.

Autophagy: Mechanisms and Therapeutic Potential of Flavonoids in Cancer

“…On the other hand, the metastasis-suppressive role of autophagy during the tumor cellular process involves selectively downregulating the key transcription factors or proteins of EMT in the early stage of tumorigenesis [ 105 ]. Autophagy caused by nutritional deprivation or inhibition of related mechanism targets of the mTOR pathway reduces the migration and invasion of glioblastoma cells [ 107 ]. Autophagy and cell motility at the molecular level are regulated by focal adhesion kinase (FAK), FAK interacting protein 200kD (FIP200), and Paxillin (PXN) [ 103 ].…”

Correspondence on ‘Role of AMPK/mTOR-independent autophagy in clear cell renal cell carcinoma’ by Radovanovic et al

“…5 9 Conversely, induction of autophagy has been shown to restrain the growth and progression of tumor cells in several cancers, including breast cancer, hepatocellular carcinoma and RCC. [10][11][12] In line with this, a study by Li et al 13 showed the anti-metastatic effect of autophagy induction in an adenocarcinoma; renal cell (ACNH) and 786-O RCC cell model-based study. In contrast to the work by Radovanovic and colleagues, this study demonstrated that the AMPK/mTOR pathway was involved in autophagy induction.…”

“…Autophagy can support the energy requirement of cancer cells for growth and metastasis 5 9. Conversely, induction of autophagy has been shown to restrain the growth and progression of tumor cells in several cancers, including breast cancer, hepatocellular carcinoma and RCC 10-12. In line with this, a study by Li et al 13 showed the anti-metastatic effect of autophagy induction in an adenocarcinoma; renal cell (ACNH) and 786-O RCC cell model-based study.…”

Plant Polyphenols for Aging Health: Implication from Their Autophagy Modulating Properties in Age-Associated Diseases

“…Silibinin attenuated the cancer cell metastasis and epithelial to mesenchymal transition through the autophagy-dependent (AMPK/mTOR) downregulation of the Wnt/β-catenin pathway. β-catenin has been previously reported to be degraded through the autophagy-lysosome system, which might have resulted in suppressing the signalling pathway [ 184 , 185 ]. In human colon cancer cells (both primary and metastatic), silibinin treatment activated both extrinsic (TRAIL receptors, caspase-8, 10, Bid) and intrinsic (cytochrome-c, caspase-9) apoptotic pathways associated with induction of cytoprotective autophagy [ 186 ].…”