Role and Inhibition of GLI1 Protein in Cancer

the Oncology Nurse Advisor take:

Inhibition of the GLI1 protein — in combination with other chemotherapeutic agents — may potentially be an effective treatment option for patients with small and non-small cell lung cancers (SCLC, NSCLC), according to this review from researchers at Universitá degli Studi di Milano, in Milan, Italy.

The Hedgehog (Hh) pathway, initiated by the SHH, IHH, and DHH genes, play a pivotal role in cell proliferation, apoptosis, differentiation, migration, and also interacts with multiple signaling pathways including MAPK/ERK, PI3K/AKT/mTOR, EGFR, and NOTCH. The SHh pathway in particular is crucial for embryonic development and has been the subject of most investigations.

Of the involved transcriptional activator proteins in the Hh pathway, GLI1 activates many downstream proteins, including the proto-oncogene N-myc and cyclin D. GLI1 is commonly overexpressed in both SCLC and NSCLC, and limiting GL1 activity may inhibit cell growth and promote apoptotic activity.

For this review, the authors present the role of GLI1 in cancer development and how its inhibition may be an effective therapy in lung cancer.

Lung Cancer: Targets and Therapy

Abstract: GLI1 is a transcriptional regulator involved in the development of different types of cancer. GLI1 transcriptional activity is regulated within the Hedgehog pathway (canonical activity), but can also be controlled independently (non-canonical activity) in the context of other signaling pathways. Experimental evidences show GLI1 involvement in both small- and non–small-cell lung cancers. Direct inhibition of the protein, in combination with other chemotherapeutic agents, represents a promising strategy for the treatment of different malignancies.

Keywords: Hedgehog pathway, transcriptional regulator, lung cancer, inhibitors

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INTRODUCTION

GLI1 is a transcriptional factor component of the canonical and non-canonical Hedgehog (Hh) pathway. Hh signaling is evolutionarily conserved in Drosophila melanogaster and superior vertebrates. In mammals, three different Hh genes have been described as initiators of the signaling pathway: SHH, IHH, and DHH – each with a characteristic role and distribution.^1,2 IHH and DHH have been shown to play important roles in normal tissue development, including bone formation and the pancreas, respectively. The SHh signaling pathway (initiated by the SHH glycoprotein) is the most studied, and it plays an essential role in the embryonic development required for appropriate cell differentiation and maintenance of tissue polarity.³

SHh-mediated transduction is activated through the binding of SHH to the PTCH.⁴ PTCH, in the absence of the SHH ligands, inhibits the activity of seven-transmembrane G-protein-coupled receptor like Smoothened (SMO). After SSH binding, PTCH inhibition of SMO is released, with resultant phosphorylation and nuclear translocation of the zinc finger (ZF) glioma-associated transcription factors GLI1, GLI2, and GLI3, which are terminal effectors of SHh signaling (Figure 1).

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Role and Inhibition of GLI1 Protein in Cancer

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INTRODUCTION

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