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Gli as a novel therapeutic target in malignant pleural mesothelioma.
- Source :
-
PloS one [PLoS One] 2013; Vol. 8 (3), pp. e57346. Date of Electronic Publication: 2013 Mar 06. - Publication Year :
- 2013
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Abstract
- Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis. Current treatment is rarely curative, thus novel meaningful therapies are urgently needed. Inhibition of Hedgehog (Hh) signaling at the cell membrane level in several cancers has shown anti-cancer activity in recent clinical studies. Evidence of Hh-independent Gli activation suggests Gli as a more potent therapeutic target. The current study is aimed to evaluate the potential of Gli as a therapeutic target to treat MPM. The expression profiles of Gli factors and other Hh signaling components were characterized in 46 MPM patient tissue samples by RT-PCR and immunohistochemistry. Cultured cell lines were employed to investigate the requirement of Gli activation in tumor cell growth by inhibiting Gli through siRNA or a novel small molecule Gli inhibitor (Gli-I). A xenograft model was used to evaluate Gli-I in vivo. In addition, a side by side comparison between Gli and Smoothened (Smo) inhibition was conducted in vitro using siRNA and small molecule inhibitors. Our study reported aberrant Gli1 and Gli2 activation in a large majority of tissues. Inhibition of Gli by siRNAs or Gli-I suppressed cell growth dramatically both in vitro and in vivo. Inhibition of Gli exhibited better cytotoxicity than that of Smo by siRNA and small molecule inhibitors vismodegib and cyclopamine. Combination of Gli-I and pemetrexed, as well as Gli-I and vismodegib demonstrated synergistic effects in suppression of MPM proliferation in vitro. In summary, Gli activation plays a critical role in MPM. Inhibition of Gli function holds strong potential to become a novel, clinically effective approach to treat MPM.
- Subjects :
- Aged
Anilides pharmacology
Anilides therapeutic use
Animals
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Down-Regulation drug effects
Down-Regulation genetics
Drug Synergism
Female
Gene Expression Regulation, Neoplastic drug effects
Glutamates pharmacology
Glutamates therapeutic use
Guanine analogs & derivatives
Guanine pharmacology
Guanine therapeutic use
Hedgehog Proteins metabolism
Humans
Kruppel-Like Transcription Factors genetics
Kruppel-Like Transcription Factors metabolism
Male
Mesothelioma genetics
Mesothelioma pathology
Mice
Mice, Nude
Nuclear Proteins genetics
Nuclear Proteins metabolism
Pemetrexed
Pleural Neoplasms genetics
Pleural Neoplasms pathology
Pyridines pharmacology
Pyridines therapeutic use
RNA, Small Interfering metabolism
Receptors, G-Protein-Coupled antagonists & inhibitors
Receptors, G-Protein-Coupled metabolism
Signal Transduction drug effects
Signal Transduction genetics
Smoothened Receptor
Transcription Factors genetics
Transcription Factors metabolism
Xenograft Model Antitumor Assays
Zinc Finger Protein GLI1
Zinc Finger Protein Gli2
Kruppel-Like Transcription Factors antagonists & inhibitors
Mesothelioma drug therapy
Molecular Targeted Therapy
Nuclear Proteins antagonists & inhibitors
Pleural Neoplasms drug therapy
Transcription Factors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23483902
- Full Text :
- https://doi.org/10.1371/journal.pone.0057346