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Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy.

Pandolfi S, Stecca B - Expert Rev Mol Med (2015)

Bottom Line: HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose activity is finely tuned by a number of molecular interactions and post-translation modifications.Several reports suggest that the activity of the GLI proteins is regulated by several proliferative and oncogenic inputs, in addition or independent of upstream HH signalling.We then summarise the latest advances on SMO and GLI inhibitors and alternative approaches to attenuate HH signalling through rational combinatorial therapies.

View Article: PubMed Central - PubMed

Affiliation: Core Research Laboratory,Istituto Toscano Tumori,Florence,Italy.

ABSTRACT
The HEDGEHOG-GLI (HH-GLI) signalling is a key pathway critical in embryonic development, stem cell biology and tissue homeostasis. In recent years, aberrant activation of HH-GLI signalling has been linked to several types of cancer, including those of the skin, brain, lungs, prostate, gastrointestinal tract and blood. HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose activity is finely tuned by a number of molecular interactions and post-translation modifications. Several reports suggest that the activity of the GLI proteins is regulated by several proliferative and oncogenic inputs, in addition or independent of upstream HH signalling. The identification of this complex crosstalk and the understanding of how the major oncogenic signalling pathways interact in cancer is a crucial step towards the establishment of efficient targeted combinatorial treatments. Here we review recent findings on the cooperative integration of HH-GLI signalling with the major oncogenic inputs and we discuss how these cues modulate the activity of the GLI proteins in cancer. We then summarise the latest advances on SMO and GLI inhibitors and alternative approaches to attenuate HH signalling through rational combinatorial therapies.

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Related in: MedlinePlus

Targeting aberrant HH-GLI pathway. HH-GLI antagonists, classified according to what level of the pathway they inhibit: SMO translocation and activation (blue); HH/PTCH interaction (orange); GLI nuclear translocation and transcriptional activity (red). Abbreviations: aPKC-i, atypical protein kinase C-inhibitor; ATO, arsenic trioxide; BET-i, BET bromodomain inhibitor; HDAC-i, histone deacetylase-inhibitors; HH, hedgehog; HPI-1/4, hedgehog pathway inhibitors 1–4; mTOR-i, mammalian target of rapamycin inhibitors; PTCH, Patched; SMO, Smoothened; SUFU, Suppressor of Fused; WIP1-i, wild-type p53-induced phosphatase 1-inhibitors. See the main text for details.
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fig03: Targeting aberrant HH-GLI pathway. HH-GLI antagonists, classified according to what level of the pathway they inhibit: SMO translocation and activation (blue); HH/PTCH interaction (orange); GLI nuclear translocation and transcriptional activity (red). Abbreviations: aPKC-i, atypical protein kinase C-inhibitor; ATO, arsenic trioxide; BET-i, BET bromodomain inhibitor; HDAC-i, histone deacetylase-inhibitors; HH, hedgehog; HPI-1/4, hedgehog pathway inhibitors 1–4; mTOR-i, mammalian target of rapamycin inhibitors; PTCH, Patched; SMO, Smoothened; SUFU, Suppressor of Fused; WIP1-i, wild-type p53-induced phosphatase 1-inhibitors. See the main text for details.

Mentions: Current HH pathway antagonists can be classified according to what level of the pathway they modulate: (i) HH/PTCH interaction; (ii) SMO translocation and activation; (iii) GLI nuclear translocation and transcriptional activation (Fig. 3).Figure 3.


Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy.

Pandolfi S, Stecca B - Expert Rev Mol Med (2015)

Targeting aberrant HH-GLI pathway. HH-GLI antagonists, classified according to what level of the pathway they inhibit: SMO translocation and activation (blue); HH/PTCH interaction (orange); GLI nuclear translocation and transcriptional activity (red). Abbreviations: aPKC-i, atypical protein kinase C-inhibitor; ATO, arsenic trioxide; BET-i, BET bromodomain inhibitor; HDAC-i, histone deacetylase-inhibitors; HH, hedgehog; HPI-1/4, hedgehog pathway inhibitors 1–4; mTOR-i, mammalian target of rapamycin inhibitors; PTCH, Patched; SMO, Smoothened; SUFU, Suppressor of Fused; WIP1-i, wild-type p53-induced phosphatase 1-inhibitors. See the main text for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836208&req=5

fig03: Targeting aberrant HH-GLI pathway. HH-GLI antagonists, classified according to what level of the pathway they inhibit: SMO translocation and activation (blue); HH/PTCH interaction (orange); GLI nuclear translocation and transcriptional activity (red). Abbreviations: aPKC-i, atypical protein kinase C-inhibitor; ATO, arsenic trioxide; BET-i, BET bromodomain inhibitor; HDAC-i, histone deacetylase-inhibitors; HH, hedgehog; HPI-1/4, hedgehog pathway inhibitors 1–4; mTOR-i, mammalian target of rapamycin inhibitors; PTCH, Patched; SMO, Smoothened; SUFU, Suppressor of Fused; WIP1-i, wild-type p53-induced phosphatase 1-inhibitors. See the main text for details.
Mentions: Current HH pathway antagonists can be classified according to what level of the pathway they modulate: (i) HH/PTCH interaction; (ii) SMO translocation and activation; (iii) GLI nuclear translocation and transcriptional activation (Fig. 3).Figure 3.

Bottom Line: HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose activity is finely tuned by a number of molecular interactions and post-translation modifications.Several reports suggest that the activity of the GLI proteins is regulated by several proliferative and oncogenic inputs, in addition or independent of upstream HH signalling.We then summarise the latest advances on SMO and GLI inhibitors and alternative approaches to attenuate HH signalling through rational combinatorial therapies.

View Article: PubMed Central - PubMed

Affiliation: Core Research Laboratory,Istituto Toscano Tumori,Florence,Italy.

ABSTRACT
The HEDGEHOG-GLI (HH-GLI) signalling is a key pathway critical in embryonic development, stem cell biology and tissue homeostasis. In recent years, aberrant activation of HH-GLI signalling has been linked to several types of cancer, including those of the skin, brain, lungs, prostate, gastrointestinal tract and blood. HH-GLI signalling is initiated by binding of HH ligands to the transmembrane receptor PATCHED and is mediated by transcriptional effectors that belong to the GLI family, whose activity is finely tuned by a number of molecular interactions and post-translation modifications. Several reports suggest that the activity of the GLI proteins is regulated by several proliferative and oncogenic inputs, in addition or independent of upstream HH signalling. The identification of this complex crosstalk and the understanding of how the major oncogenic signalling pathways interact in cancer is a crucial step towards the establishment of efficient targeted combinatorial treatments. Here we review recent findings on the cooperative integration of HH-GLI signalling with the major oncogenic inputs and we discuss how these cues modulate the activity of the GLI proteins in cancer. We then summarise the latest advances on SMO and GLI inhibitors and alternative approaches to attenuate HH signalling through rational combinatorial therapies.

Show MeSH
Related in: MedlinePlus