Inactivation of the Transcription Factor GLI1 Accelerates Pancreatic Cancer Progression

Mills, Lisa D.; Zhang, Lizhi; Marler, Ronald J.; Svingen, Phyllis A.; Fernández‐Barrena, Maite G.; Dave, Maneesh; Bamlet, William R.; McWilliams, Robert R.; Petersen, Gloria M.; Faubion, William A.; Fernández-Zapico, Martín E.

doi:10.1074/jbc.m113.539031

Cited by 24 publications

(10 citation statements)

References 59 publications

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“…On the other side, overactivated Hh signaling is associated with the development of basal cell carcinoma and medulloblastoma [ 66 , 67 ], but evidence for a tumor-restraining activity of (mostly stromal) Hh signaling has also been provided for pancreatic [ 68 , 69 , 70 ], colon [ 71 ] and pulmonary [ 72 , 73 , 74 ] malignancies. Another example where Hh exerts tumor-suppressive effects is neuroblastoma (NB), the most frequent solid cancer in infants and young children [ 16 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Koeniger

Brichkina

Nee

et al. 2021

Cancers

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Although being rare in absolute numbers, neuroblastoma (NB) represents the most frequent solid tumor in infants and young children. Therapy options and prognosis are comparably good for NB patients except for the high risk stage 4 class. Particularly in adolescent patients with certain genetic alterations, 5-year survival rates can drop below 30%, necessitating the development of novel therapy approaches. The developmentally important Hedgehog (Hh) pathway is involved in neural crest differentiation, the cell type being causal in the etiology of NB. However, and in contrast to its function in some other cancer types, Hedgehog signaling and its transcription factor GLI1 exert tumor-suppressive functions in NB, rendering GLI1 an interesting new candidate for anti-NB therapy. Unfortunately, the therapeutic concept of pharmacological Hh/GLI1 pathway activation is difficult to implement as NB cells have lost primary cilia, essential organelles for Hh perception and activation. In order to bypass this bottleneck, we have identified a GLI1-activating small molecule which stimulates endogenous GLI1 production without the need for upstream Hh pathway elements such as Smoothened or primary cilia. This isoxazole compound potently abrogates NB cell proliferation and might serve as a starting point for the development of a novel class of NB-suppressive molecules.

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Section: Discussionmentioning

confidence: 99%

Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Koeniger

Brichkina

Nee

et al. 2021

Cancers

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“…During the process of apoptosis, cells undergo several characteristic morphological changes such as cell shrinkage, nuclear/chromatin condensation, membrane blebbing and formation of apoptotic bodies [ 28 , 29 , 30 ]. One of the mechanisms responsible for apoptotic morphological changes is the activation of proteases, such as those of the caspase family, whose activation is considered to be an early marker of apoptosis [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Involvement of JNK and Caspase Activation in Hoiamide A-Induced Neurotoxicity in Neocortical Neurons

Cao

Zou

et al. 2015

Marine Drugs

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The frequent occurrence of Moorea producens (formerly Lyngbya majuscula) blooms has been associated with adverse effects on human health. Hoiamide A is a structurally unique cyclic depsipeptide isolated from an assemblage of the marine cyanobacteria M. producens and Phormidium gracile. We examined the influence of hoiamide A on neurite outgrowth in neocortical neurons and found that it suppressed neurite outgrowth with an IC50 value of 4.89 nM. Further study demonstrated that hoiamide A stimulated lactic acid dehydrogenase (LDH) efflux, nuclear condensation and caspase-3 activity with EC50 values of 3.66, 2.55 and 4.33 nM, respectively. These data indicated that hoiamide A triggered a unique neuronal death profile that involves both necrotic and apoptotic mechanisms. The similar potencies and similar time-response relationships between LDH efflux and caspase-3 activation/nuclear condensation suggested that both necrosis and apoptosis may derive from interaction with a common molecular target. The broad-spectrum caspase inhibitor, Z-VAD-FMK completely inhibited hoiamide A-induced neurotoxicity. Additionally, hoiamide A stimulated JNK phosphorylation, and a JNK inhibitor attenuated hoiamide A-induced neurotoxicity. Collectively, these data demonstrate that hoiamide A-induced neuronal death requires both JNK and caspase signaling pathways. The potent neurotoxicity and unique neuronal cell death profile of hoiamide A represents a novel neurotoxic chemotype from marine cyanobacteria.

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“…The importance of tumor stroma-derived SHH signaling has been demonstrated in medulloblastoma and in K-RAS transgenic pancreatic cancer mice, both models representing aggressive incurable cancers (65)(66)(67). Lack of GLI1 in the tumor microenvironment of KRAS mice markedly reduced cancer cell growth (68).…”

Section: Sonic Hedgehog In Tissue Injury and Cancermentioning

confidence: 99%

TGF-beta1 WNT and SHH signaling in tumor progression and in fibrotic diseases

Castellone

Laukkanen

2017

Front Biosci

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Activation of resting fibroblasts to myofibroblasts characterizes several physiological and pathological conditions, from wound healing to aggressive metastatic cancers. In tissue damage, including wound healing, fibroblasts are activated in response to injury for a limited period of time to stimulate the healing process. Similar biological mechanisms are maintained in pathological conditions, e.g., scleroderma and cancer, where myofibroblasts persist in producing cytokines and growth factors to drive the development of fibrosis and the progression of disease. Studies characterizing the bi-directional signal transduction pathways between cancer cells and stromal cells have suggested novel druggable targets that may function in both the inhibition of fibrotic reactions in cancer stroma and in the inhibition of fibrotic diseases. In this review, we focus on transforming growth factor beta (TGF-beta), int/Wingless (WNT), and sonic hedgehog (SHH) signal transduction pathways and describe small molecule inhibitors that are used in phase I/II clinical trials to treat fibrosis or fibrotic cancers.

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Inactivation of the Transcription Factor GLI1 Accelerates Pancreatic Cancer Progression

Cited by 24 publications

References 59 publications

Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Involvement of JNK and Caspase Activation in Hoiamide A-Induced Neurotoxicity in Neocortical Neurons

TGF-beta1 WNT and SHH signaling in tumor progression and in fibrotic diseases

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