Abstract
The downstream transcriptional factor of the hedgehog(Hh) pathway, GLI family zinc finger1(GLI1), plays a crucial role in regulating tumor progression. In the present study, we demonstrated that silibinin, a natural flavonoid antioxidant isolated from extracts of the milk thistle herb, exerts its anticancer capabilities by restraining GLI1 function in renal cell carcinoma(RCC) cells invitro and invivo. In the present study, we confirmed that silibinin induced growth inhibition of RCC through caspase-dependent apoptosis and downregulation of GLI1 and BCL2, which could be partially reversed by GLI1 overexpression. Moreover, we determined that the decreased GLI1 expression by silibinin was mediated by the mammalian target of rapamycin(mTOR) pathway. The invivo mouse xenograft study also showed that silibinin significantly reduced RCC tumor growth and specifically targeted the mTOR-GLI1-BCL2 signaling pathway. In conclusion, our findings demonstrated for the first time that silibinin induces apoptosis of RCC cells through inhibition of the mTOR-GLI1‑BCL2 pathway. These findings also indicate that GLI1 is a novel regulator for the potential therapeutic application of silibinin against RCC.
Highlights
Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system, accounting for 80-90% of kidney neoplasms
Human RCC cell lines 769-P, 786-O, ACHN and OS-RC-2 were purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA), and cultured in Dulbecco's modified Eagle's medium (DMEM)/F-12 medium supplemented with 10% fetal bovine serum (FBS) (Gibco-BRL, New York, NY, USA) at 37 ̊C, in humidified air containing 5% CO2
The results showed that silibinin significantly inhibited the proliferation of RCC cells in a dose- and time-dependent manner as detected by MTT assay (Fig. 1A)
Summary
Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system, accounting for 80-90% of kidney neoplasms. The American Cancer Society estimated that the number of new cancer cases and deaths caused by cancer of the kidney and renal pelvis were 63,920 and 13,860 in 2014 in the US [1]. Surgical resection is considered to be the first choice for the curative treatment of localized RCC and some locally advanced RCC. Understanding the mechanisms involved in the progression of RCC especially mRCC and exploring more effective targeted therapies are urgently needed
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