Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding

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Abstract

The GLI genes, GLI1 and GLI2, are transcription factors that regulate target genes at the distal end of the canonical Hedgehog (HH) signaling pathway (SHH->PTCH->SMO->GLI), tightly regulated in embryonic development, tissue patterning and differentiation. Both GLI1 and GLI2 are oncogenes, constitutively activated in many types of human cancers. In colon cancer cells oncogenic KRAS-GLI signaling circumvents the HH-SMO-GLI axis to channel through and activate GLI in the transcriptional regulation of target genes. We have observed extensive cell death in a panel of 7 human colon carcinoma cell lines using the small molecule GLI inhibitor GANT61. Using computational docking and experimental confirmation by Surface Plasmon Resonance, GANT61 binds to the 5-zinc finger GLI1 protein between zinc fingers 2 and 3 at sites E119 and E167, independent of the GLI-DNA binding region, and conserved between GLI1 and GLI2. GANT61 does not bind to other zinc finger transcription factors (KLF4, TFIIβ). Mutating the predicted GANT61 binding sites in GLI1 significantly inhibits GANT61-GLI binding and GLI-luciferase activity. Data establish the specificity of GANT61 for targeting GLI, and substantiate the critical role of GLI in cancer cell survival. Thus, targeting GLI in cancer therapeutics may be of high impact.

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Most cited references 60

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The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions.

Seunghee Yoon, Rony Seger (2006)

The extracellular signal-regulated kinase (ERK) cascade is a central pathway that transmits signals from many extracellular agents to regulate cellular processes such as proliferation, differentiation and cell cycle progression. The signaling via the ERK cascade is mediated by sequential phosphorylation and activation of protein kinases in the different tiers of the cascade. Although the main core phosphorylation chain of the cascade includes Raf kinases, MEK1/2, ERK1/2 (ERKs) and RSKs, other alternatively spliced forms and distinct components exist in the different tiers, and participate in ERK signaling under specific conditions. These components enhance the complexity of the ERK cascade and thereby, enable the wide variety of functions that are regulated by it. Another factor that is important for the dissemination of ERKs' signals is the multiplicity of the cascade's substrates, which include transcription factors, protein kinases and phosphatases, cytoskeletal elements, regulators of apoptosis, and a variety of other signaling-related molecules. About 160 substrates have already been discovered for ERKs, and the list of these substrates, as well as the function and mechanism of activation of representative substrates, are described in the current review. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Understanding of these processes may provide a full picture of the distinct, and even opposing cellular processes that are regulated by the ERK cascade.

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American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy.

Carmen J Allegra, J. Milburn Jessup, Mark Somerfield … (2009)

An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO), offers timely clinical direction to ASCO's oncologists following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the utility of KRAS gene mutation testing in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MoAb) therapy with cetuximab or panitumumab (see Note). Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with monoclonal antibodies directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy. Five randomized controlled trials of cetuximab or panitumumab have evaluated outcomes for patients with metastatic colorectal carcinoma in relation to KRAS mutational status as no mutation detected (wild type) or abnormal (mutated). Another five single-arm studies have retrospectively evaluated tumor response according to KRAS status. Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written, and are intended to assist physicians in clinical decision-making and identify questions and settings for further research. Due to the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.

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Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists.

Matthias Lauth, Åsa Bergström, Takashi Shimokawa … (2007)

The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: June 2014

Publication date (Electronic): 31 May 2014

Volume: 5

Issue: 12

Pages: 4492-4503

Affiliations

¹ Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH

Author notes

Correspondence to: Janet A. Houghton, houghtj@ 123456ccf.org

Article

DOI: 10.18632/oncotarget.2046

PMC ID: 4147340

PubMed ID: 24962990

SO-VID: 618c6f16-a053-474a-bf77-f5303eb9b186

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding

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Karger: Oncology

Most cited references 60

The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions.

American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy.

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists.

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