1. Gli as a novel therapeutic target in malignant pleural mesothelioma.
- Author
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Li H, Lui N, Cheng T, Tseng HH, Yue D, Giroux-Leprieur E, Do HT, Sheng Q, Jin JQ, Luh TW, Jablons DM, and He B
- 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
- 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.
- Published
- 2013
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