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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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Cooperative integration between HH-GLI signalling and other oncogenic pathways. (a) Schematic diagram of the basic components of the HH-GLI signalling (filled circles) and their positive (in green) and negative regulators (in red) (unfilled circles). (b) Direct transcriptional regulators of GLI1, GLI2 and SHH. See text for further details. Abbreviations: AKT, v-akt murine thymoma viral oncogene homologue; aPKCι/λ, atypical protein kinase C-ι/λ; β-CAT, β-catenin; DYRK1/2, dual specificity Yak-1 related kinase 1/2; ERα, oestrogen receptor α; EWS/FLI1, Ewing's sarcoma/friend leukaemia integration 1 transcription factor fusion gene; HES1, hairy and enhancer of split-1; HH, Hedgehog; mTOR, mammalian target of rapamycin; MEF2C, myocyte enhancer factor 2C; MEK, mitogen-activated protein/extracellular signal-regulated kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRP1/2, neuropilin; PI3K, phosphoinositide-3-kinase; PKA, protein kinase A; PTCH, Patched; PTEN, phosphatase and tensin homologue; RACK1, receptor for activated C kinase 1; RTK, receptor tyrosine kinase; S6K1, ribosomal protein S6 kinase 1; SHH, Sonic hedgehog; SMO, Smoothened; SUFU, Suppressor of Fused; TNFα, tumour necrosis factor α; TSC1/2, tuberous sclerosis 1/2; WIP1, wild-type p53-induced phosphatase 1.
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fig02: Cooperative integration between HH-GLI signalling and other oncogenic pathways. (a) Schematic diagram of the basic components of the HH-GLI signalling (filled circles) and their positive (in green) and negative regulators (in red) (unfilled circles). (b) Direct transcriptional regulators of GLI1, GLI2 and SHH. See text for further details. Abbreviations: AKT, v-akt murine thymoma viral oncogene homologue; aPKCι/λ, atypical protein kinase C-ι/λ; β-CAT, β-catenin; DYRK1/2, dual specificity Yak-1 related kinase 1/2; ERα, oestrogen receptor α; EWS/FLI1, Ewing's sarcoma/friend leukaemia integration 1 transcription factor fusion gene; HES1, hairy and enhancer of split-1; HH, Hedgehog; mTOR, mammalian target of rapamycin; MEF2C, myocyte enhancer factor 2C; MEK, mitogen-activated protein/extracellular signal-regulated kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRP1/2, neuropilin; PI3K, phosphoinositide-3-kinase; PKA, protein kinase A; PTCH, Patched; PTEN, phosphatase and tensin homologue; RACK1, receptor for activated C kinase 1; RTK, receptor tyrosine kinase; S6K1, ribosomal protein S6 kinase 1; SHH, Sonic hedgehog; SMO, Smoothened; SUFU, Suppressor of Fused; TNFα, tumour necrosis factor α; TSC1/2, tuberous sclerosis 1/2; WIP1, wild-type p53-induced phosphatase 1.

Mentions: The activity of HH-GLI signalling observed in human cancer is the result of its functional interaction with other pathways and of the direct or indirect regulation of the final effectors of the HH signalling by oncogenes and tumour suppressors (Fig. 2). Multiple lines of evidence support an interplay between HH-GLI and PI3K/AKT or RAS/RAF/MEK signalling. PI3K/AKT negatively regulates the degradation of GLI2 by interfering with PKA/GSK3β-mediated phosphorylation of GLI2, which targets the protein to proteasome-mediated degradation (Ref. 189). In zebrafish, a constitutively active form of Akt1 synergises with activated Smo in tumour formation (Ref. 190). AKT1 potentiates GLI1 transcriptional activity and nuclear localisation in melanoma cells (Ref. 78). In contrast, GLI1 function is inhibited by PI3K/AKT2 signalling in neuroblastoma; AKT2 phosphorylates GSK3β and prevents the destabilisation of SUFU, resulting in reduced GLI1 nuclear localisation and transcriptional activity (Ref. 191).Figure 2.


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

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

Cooperative integration between HH-GLI signalling and other oncogenic pathways. (a) Schematic diagram of the basic components of the HH-GLI signalling (filled circles) and their positive (in green) and negative regulators (in red) (unfilled circles). (b) Direct transcriptional regulators of GLI1, GLI2 and SHH. See text for further details. Abbreviations: AKT, v-akt murine thymoma viral oncogene homologue; aPKCι/λ, atypical protein kinase C-ι/λ; β-CAT, β-catenin; DYRK1/2, dual specificity Yak-1 related kinase 1/2; ERα, oestrogen receptor α; EWS/FLI1, Ewing's sarcoma/friend leukaemia integration 1 transcription factor fusion gene; HES1, hairy and enhancer of split-1; HH, Hedgehog; mTOR, mammalian target of rapamycin; MEF2C, myocyte enhancer factor 2C; MEK, mitogen-activated protein/extracellular signal-regulated kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRP1/2, neuropilin; PI3K, phosphoinositide-3-kinase; PKA, protein kinase A; PTCH, Patched; PTEN, phosphatase and tensin homologue; RACK1, receptor for activated C kinase 1; RTK, receptor tyrosine kinase; S6K1, ribosomal protein S6 kinase 1; SHH, Sonic hedgehog; SMO, Smoothened; SUFU, Suppressor of Fused; TNFα, tumour necrosis factor α; TSC1/2, tuberous sclerosis 1/2; WIP1, wild-type p53-induced phosphatase 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: Cooperative integration between HH-GLI signalling and other oncogenic pathways. (a) Schematic diagram of the basic components of the HH-GLI signalling (filled circles) and their positive (in green) and negative regulators (in red) (unfilled circles). (b) Direct transcriptional regulators of GLI1, GLI2 and SHH. See text for further details. Abbreviations: AKT, v-akt murine thymoma viral oncogene homologue; aPKCι/λ, atypical protein kinase C-ι/λ; β-CAT, β-catenin; DYRK1/2, dual specificity Yak-1 related kinase 1/2; ERα, oestrogen receptor α; EWS/FLI1, Ewing's sarcoma/friend leukaemia integration 1 transcription factor fusion gene; HES1, hairy and enhancer of split-1; HH, Hedgehog; mTOR, mammalian target of rapamycin; MEF2C, myocyte enhancer factor 2C; MEK, mitogen-activated protein/extracellular signal-regulated kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRP1/2, neuropilin; PI3K, phosphoinositide-3-kinase; PKA, protein kinase A; PTCH, Patched; PTEN, phosphatase and tensin homologue; RACK1, receptor for activated C kinase 1; RTK, receptor tyrosine kinase; S6K1, ribosomal protein S6 kinase 1; SHH, Sonic hedgehog; SMO, Smoothened; SUFU, Suppressor of Fused; TNFα, tumour necrosis factor α; TSC1/2, tuberous sclerosis 1/2; WIP1, wild-type p53-induced phosphatase 1.
Mentions: The activity of HH-GLI signalling observed in human cancer is the result of its functional interaction with other pathways and of the direct or indirect regulation of the final effectors of the HH signalling by oncogenes and tumour suppressors (Fig. 2). Multiple lines of evidence support an interplay between HH-GLI and PI3K/AKT or RAS/RAF/MEK signalling. PI3K/AKT negatively regulates the degradation of GLI2 by interfering with PKA/GSK3β-mediated phosphorylation of GLI2, which targets the protein to proteasome-mediated degradation (Ref. 189). In zebrafish, a constitutively active form of Akt1 synergises with activated Smo in tumour formation (Ref. 190). AKT1 potentiates GLI1 transcriptional activity and nuclear localisation in melanoma cells (Ref. 78). In contrast, GLI1 function is inhibited by PI3K/AKT2 signalling in neuroblastoma; AKT2 phosphorylates GSK3β and prevents the destabilisation of SUFU, resulting in reduced GLI1 nuclear localisation and transcriptional activity (Ref. 191).Figure 2.

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