A highlight on Sonic hedgehog pathway

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Abstract

Hedgehog (Hh) signaling pathway plays an essential role during vertebrate embryonic development and tumorigenesis. It is already known that Sonic hedgehog (Shh) pathway is important for the evolution of radio and chemo-resistance of several types of tumors. Most of the brain tumors are resistant to chemotherapeutic drugs, consequently, they have a poor prognosis. So, a better knowledge of the Shh pathway opens an opportunity for targeted therapies against brain tumors considering a multi-factorial molecular overview. Therefore, emerging studies are being conducted in order to find new inhibitors for Shh signaling pathway, which could be safely used in clinical trials. Shh can signal through a canonical and non-canonical way, and it also has important points of interaction with other pathways during brain tumorigenesis. So, a better knowledge of Shh signaling pathway opens an avenue of possibilities for the treatment of not only for brain tumors but also for other types of cancers. In this review, we will also highlight some clinical trials that use the Shh pathway as a target for treating brain cancer.

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Most cited references 97

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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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Ubiquitin and ubiquitin-like proteins as multifunctional signals.

Rebecca L Welchman, Colin Gordon, R. Mayer (2005)

Protein ubiquitylation is a recognized signal for protein degradation. However, it is increasingly realized that ubiquitin conjugation to proteins can be used for many other purposes. Furthermore, there are many ubiquitin-like proteins that control the activities of proteins. The central structural element of these post-translational modifications is the ubiquitin superfold. A common ancestor based on this superfold has evolved to give various proteins that are involved in diverse activities in the cell.

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Sonic hedgehog regulates the growth and patterning of the cerebellum.

N Dahmane, A Ruiz i Altaba (1999)

The molecular bases of brain development and CNS malignancies remain poorly understood. Here we show that Sonic hedgehog (Shh) signaling controls the development of the cerebellum at multiple levels. SHH is produced by Purkinje neurons, it is required for the proliferation of granule neuron precursors and it induces the differentiation of Bergmann glia. Blocking SHH function in vivo results in deficient granule neuron and Bergmann glia differentiation as well as in abnormal Purkinje neuron development. Thus, our findings provide a molecular model for the growth and patterning of the cerebellum by SHH through the coordination of the development of cortical cerebellar cell types. In addition, they provide a cellular context for medulloblastomas, childhood cancers of the cerebellum.

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Author and article information

Contributors

Tania Cristina Leite de Sampaio e Spohr: +552 122 779 393 , tcpohr@gmail.com

Journal

Journal ID (nlm-ta): Cell Commun Signal

Journal ID (iso-abbrev): Cell Commun. Signal

Title: Cell Communication and Signaling : CCS

Publisher: BioMed Central (London )

ISSN (Electronic): 1478-811X

Publication date (Electronic): 20 March 2018

Publication date PMC-release: 20 March 2018

Publication date Collection: 2018

Volume: 16

Electronic Location Identifier: 11

Affiliations

[1 ]Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230–024 Brazil

[2 ]GRID grid.419166.d, Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação de Pesquisa, , Instituto Nacional de Câncer (INCA), ; RJ, Brazil

[3 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Programa de Pós-Gradução em Anatomia Patológica, , Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, ; Rio de Janeiro, Brazil

Article

Publisher ID: 220

DOI: 10.1186/s12964-018-0220-7

PMC ID: 5861627

PubMed ID: 29558958

SO-VID: a66f671f-f95c-425a-aa31-078ad38c0fd2

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 5 December 2017

Date accepted : 16 February 2018

Funding

Funded by: National Institute for Translational Neuroscience (INNT) of the Ministry of Science and Technology

Funded by: Brazilian Federal Agency for the Support and Evaluation of Graduate Education (CAPES) of the Ministry of Education

Funded by: National Council for Scientific and Technological Development (CNPq)

Funded by: Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro Carlos Chagas Filho Research Support Foundation (FAPERJ)

Funded by: Ary Frauzino Foundation for Cancer Research

Funded by: Pró-Saúde Associação Beneficiente de Assistência Social e Hospitalar

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ScienceOpen disciplines: Cell biology

Keywords: sonic hedgehog pathway,canonical shh signaling,non-canonical shh signaling,clinical-trials,brain tumors

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ScienceOpen disciplines: Cell biology

Keywords: sonic hedgehog pathway, canonical shh signaling, non-canonical shh signaling, clinical-trials, brain tumors

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A highlight on Sonic hedgehog pathway

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Most cited references 97

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

Ubiquitin and ubiquitin-like proteins as multifunctional signals.

Sonic hedgehog regulates the growth and patterning of the cerebellum.

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