Gli as a Novel Therapeutic Target in Malignant Pleural Mesothelioma

Hui Li,Biao He,Qing Sheng,Joy Q Jin,Etienne Giroux-Leprieur,Tiffany Cheng,Dongsheng Yue,David M Jablons,Hanh T Do,Thomas W Luh,Hsin-Hui K Tseng,Natalie Lui,Jingwu Xie

doi:10.1371/journal.pone.0057346

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.

Highlights

Malignant pleura mesothelioma (MPM) is an uncommon but inexorably fatal cancer that arises from the surface serosal cells of the pleura and, less frequently, from the peritoneum [1,2,3]
The current study investigated the aberrant activation of Glioma-associated oncogene (Gli) proteints in MPM, explored the effectiveness of targeted inhibition by a novel Gli inhibitor (Gli-I) to inhibit MPM cell growth, and compared the efficacy of Smo and Gli inhibitors
Gli Family of Transcriptional Factors are Expressed in Malignant Pleural Mesothelioma

Summary

Introduction

Malignant pleura mesothelioma (MPM) is an uncommon but inexorably fatal cancer that arises from the surface serosal cells of the pleura and, less frequently, from the peritoneum [1,2,3]. Treatment of MPM with surgery, chemotherapy, or radiation therapy is rarely curative with a median survival ranging from 10 to months [2]. Long-term survival with currently available treatment is rare [3,4]. In spite of frequent observation of NF-kB, EGFR, and PI3K/AKT signaling deregulation in MPM cells, the molecular mechanism underlying tumorigenesis in MPM is poorly understood [1,5,6,7]. Exploring the role of the Hh pathway in MPM and inhibiting its aberrant activation holds great promise to provide novel and effective treatments for MPM patients

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Results

Conclusion