title: Gli as a novel therapeutic target in malignant pleural mesothelioma.
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.
authors.affiliation: Thoracic Oncology Program, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Natalie
authors.initials: N
authors.lastname: Lui
authors.forename: Tiffany
authors.initials: T
authors.lastname: Cheng
authors.forename: Hsin-Hui K
authors.initials: HH
authors.lastname: Tseng
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Yue
authors.forename: Etienne
authors.initials: E
authors.lastname: Giroux-Leprieur
authors.forename: Hanh T
authors.initials: HT
authors.lastname: Do
authors.forename: Qing
authors.initials: Q
authors.lastname: Sheng
authors.forename: Joy Q
authors.initials: JQ
authors.lastname: Jin
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Luh
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
authors.forename: Biao
authors.initials: B
authors.lastname: He
mesh_terms: D000368:Aged; D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C400551:GLI1 protein, human; C082593:GLI2 protein, human; D005971:Glutamates; D053823:Hedgehog Proteins; C538724:HhAntag691; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D011725:Pyridines; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000068437:Pemetrexed; D006147:Guanine