Silibinin induces apoptosis through inhibition of the mTOR-GLI1-BCL2 pathway in renal cell carcinoma.
The downstream transcriptional factor of the hedgehog (Hh) pathway, GLI family zinc finger 1 (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 in vitro and in vivo. 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 in vivo 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.
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Zhenkun
Z
Ma
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Wei
W
Liu
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Jin
J
Zeng
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Jiancheng
J
Zhou
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Peng
P
Guo
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Hongjun
H
Xie
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Zhao
Z
Yang
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Long
L
Zheng
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Shan
S
Xu
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Xinyang
X
Wang
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Luke S
LS
Chang
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Dalin
D
He
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Lei
L
Li
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C400551:GLI1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012838:Silymarin; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000077385:Silybin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3