PMID- 24423612
OWN - NLM
STAT- MEDLINE
DCOM- 20141218
LR  - 20211021
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 20
IP  - 6
DP  - 2014 Mar 15
TI  - Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung 
      cancer.
PG  - 1566-75
LID - 10.1158/1078-0432.CCR-13-2195 [doi]
AB  - PURPOSE: Lung squamous cell carcinoma (LSCC) currently lacks effective targeted 
      therapies. Previous studies reported overexpression of Hedgehog (HH)-GLI 
      signaling components in LSCC. However, they addressed neither the tumor 
      heterogeneity nor the requirement for HH-GLI signaling. Here, we investigated the 
      role of HH-GLI signaling in LSCC, and studied the therapeutic potential of HH-GLI 
      suppression. EXPERIMENTAL DESIGN: Gene expression datasets of two independent 
      LSCC patient cohorts were analyzed to study the activation of HH-GLI signaling. 
      Four human LSCC cell lines were examined for HH-GLI signaling components. Cell 
      proliferation and apoptosis were assayed in these cells after blocking the HH-GLI 
      pathway by lentiviral-shRNA knockdown or small-molecule inhibitors. Xenografts in 
      immunodeficient mice were used to determine the in vivo efficacy of GLI inhibitor 
      GANT61. RESULTS: In both cohorts, activation of HH-GLI signaling was 
      significantly associated with the classical subtype of LSCC. In cell lines, 
      genetic knockdown of Smoothened (SMO) produced minor effects on cell survival, 
      whereas GLI2 knockdown significantly reduced proliferation and induced extensive 
      apoptosis. Consistently, the SMO inhibitor GDC-0449 resulted in limited 
      cytotoxicity in LSCC cells, whereas the GLI inhibitor GANT61 was very effective. 
      Importantly, GANT61 demonstrated specific in vivo antitumor activity in xenograft 
      models of GLI(+) cell lines. CONCLUSION: Our studies demonstrate an important 
      role for GLI2 in LSCC, and suggest GLI inhibition as a novel and potent strategy 
      to treat a subset of patients with LSCC.
CI  - (c)2014 AACR.
FAU - Huang, Lingling
AU  - Huang L
AD  - Authors' Affiliations: Department of Surgery, Duke University, Durham and 
      Department of Medicine, University of North Carolina, Chapel Hill, North 
      Carolina.
FAU - Walter, Vonn
AU  - Walter V
FAU - Hayes, D Neil
AU  - Hayes DN
FAU - Onaitis, Mark
AU  - Onaitis M
LA  - eng
GR  - P30 CA016086/CA/NCI NIH HHS/United States
GR  - P41 RR005959/RR/NCRR NIH HHS/United States
GR  - T32 CA106209/CA/NCI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140114
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (GANT 61)
RN  - 0 (GLI1 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Pyridines)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (SMO protein, human)
RN  - 0 (Smoothened Receptor)
RN  - 0 (Transcription Factors)
RN  - 0 (Zinc Finger Protein GLI1)
SB  - IM
CIN - Nat Rev Clin Oncol. 2014 Mar;11(3):121. PMID: 24492832
MH  - Animals
MH  - Apoptosis/drug effects/physiology
MH  - Blotting, Western
MH  - Carcinoma, Squamous Cell/*metabolism/pathology
MH  - Gene Knockdown Techniques
MH  - Hedgehog Proteins/*metabolism
MH  - Heterografts
MH  - Humans
MH  - Lung Neoplasms/*metabolism/pathology
MH  - Mice
MH  - Pyridines/pharmacology
MH  - Pyrimidines/pharmacology
MH  - Receptors, G-Protein-Coupled/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*physiology
MH  - Smoothened Receptor
MH  - Transcription Factors/*metabolism
MH  - Zinc Finger Protein GLI1
PMC - PMC4136748
MID - NIHMS556385
EDAT- 2014/01/16 06:00
MHDA- 2014/12/19 06:00
PMCR- 2015/03/15
CRDT- 2014/01/16 06:00
PHST- 2014/01/16 06:00 [entrez]
PHST- 2014/01/16 06:00 [pubmed]
PHST- 2014/12/19 06:00 [medline]
PHST- 2015/03/15 00:00 [pmc-release]
AID - 1078-0432.CCR-13-2195 [pii]
AID - 10.1158/1078-0432.CCR-13-2195 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2014 Mar 15;20(6):1566-75. doi: 10.1158/1078-0432.CCR-13-2195. 
      Epub 2014 Jan 14.