PMID- 26323996
OWN - NLM
STAT- MEDLINE
DCOM- 20160718
LR  - 20211203
IS  - 1791-2431 (Electronic)
IS  - 1021-335X (Linking)
VI  - 34
IP  - 5
DP  - 2015 Nov
TI  - Silibinin induces apoptosis through inhibition of the mTOR-GLI1-BCL2 pathway in 
      renal cell carcinoma.
PG  - 2461-8
LID - 10.3892/or.2015.4224 [doi]
AB  - 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.
FAU - Ma, Zhenkun
AU  - Ma Z
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Liu, Wei
AU  - Liu W
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Zeng, Jin
AU  - Zeng J
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Zhou, Jiancheng
AU  - Zhou J
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Guo, Peng
AU  - Guo P
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Xie, Hongjun
AU  - Xie H
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Yang, Zhao
AU  - Yang Z
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Zheng, Long
AU  - Zheng L
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Xu, Shan
AU  - Xu S
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Wang, Xinyang
AU  - Wang X
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Chang, Luke S
AU  - Chang LS
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - He, Dalin
AU  - He D
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
FAU - Li, Lei
AU  - Li L
AD  - Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, Shaanxi 710061, P.R. China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150826
PL  - Greece
TA  - Oncol Rep
JT  - Oncology reports
JID - 9422756
RN  - 0 (Antineoplastic Agents)
RN  - 0 (BCL2 protein, human)
RN  - 0 (GLI1 protein, human)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Silymarin)
RN  - 0 (Transcription Factors)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - 4RKY41TBTF (Silybin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Apoptosis/*drug effects
MH  - Carcinoma, Renal Cell/*drug therapy/pathology
MH  - Caspase 3/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Humans
MH  - Kidney Neoplasms/*drug therapy/pathology
MH  - Male
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Signal Transduction
MH  - Silybin
MH  - Silymarin/*pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Transcription Factors/metabolism
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
MH  - Zinc Finger Protein GLI1
EDAT- 2015/09/02 06:00
MHDA- 2016/07/19 06:00
CRDT- 2015/09/02 06:00
PHST- 2015/05/08 00:00 [received]
PHST- 2015/07/22 00:00 [accepted]
PHST- 2015/09/02 06:00 [entrez]
PHST- 2015/09/02 06:00 [pubmed]
PHST- 2016/07/19 06:00 [medline]
AID - 10.3892/or.2015.4224 [doi]
PST - ppublish
SO  - Oncol Rep. 2015 Nov;34(5):2461-8. doi: 10.3892/or.2015.4224. Epub 2015 Aug 26.