Inhibition of the sonic hedgehog pathway by cyplopamine reduces the CD133+/CD15+ cell compartment and the in vitro tumorigenic capability of neuroblastoma cells

Schiapparelli, Paula; Shahi, Mehdi H.; Enguita-Germán, Mónica; Johnsen, John Inge; Kogner, Per; Lázcoz, Paula; Castresana, Javier S.

doi:10.1016/j.canlet.2011.07.005

Cited by 34 publications

(28 citation statements)

References 21 publications

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“…GAS1 is a protein involved with two major signaling pathways, namely GDNF and SHH, and in this paper, we have analyzed a potential interaction between the two intracellular signaling cascades. Abnormal SHH signaling has been associated with the origin and maintenance of neuroblastomas, and several of the components of this pathway have been detected in primary human neuroblastomas and cell lines, including SH-SY5Y [33][34][35][36]. In the present work, we detected the expression of the mRNAs for SHH, PTCH1 and GLI1, in both SH-SY5Y cells and cells expressing GAS1 mRNA antisense, in conditions of proliferation and after serum withdrawal ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 51%

GAS1 induces cell death through an intrinsic apoptotic pathway

et al. 2012

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Growth Arrest Specific 1 (GAS1) is a protein expressed when cells are arrested and during development. When ectopically expressed, GAS1 induces cell arrest and apoptosis of different cell lines, and we have previously demonstrated that the apoptotic process set off by GAS1 is caused by its capacity inhibiting the GDNF-mediated intracellular survival signaling. In the present work, we have dissected the molecular pathway leading to cell death. We employed the SH-SY5Y human neuroblastoma cell line that expresses GAS1 when deprived of serum. We observed, as we have previously described, that the presence of GAS1 reduces RET phosphorylation and inhibits the activation of AKT. We have now determined that the presence of GAS1 also triggers the dephosphorylation of BAD, which, in turn, provokes the release of Cytochrome-c from the mitochondria to the cytosol activating caspase-9, prompting the activity of caspase-3 and resulting in apoptosis of the cells. The apoptotic process is intrinsic, because there is no activation of caspase-8, thus this is consistent with apoptosis induced by the lack of trophic support. Interestingly, in cells where GAS1 has been silenced there is a significant delay in the onset of apoptosis.

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Section: Discussionmentioning

confidence: 51%

GAS1 induces cell death through an intrinsic apoptotic pathway

et al. 2012

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“…There is increasing evidence that connects the SHH/GLI pathway and tumor initiation specific markers as targets (Katoh and Katoh, 2009). In neuroblastoma, for instance, a SHH pathway pharmacological loss of function reduces a CD133/ CD15 positive compartment (Schiapparelli et al, 2011). In medulloblastoma, stem cell markers have been involved in SHH tumor propagation (Read et al, 2009), and are also directly controlled by the pathway .…”

Section: Initiationmentioning

confidence: 99%

Sonic Hedgehog in cancer stem cells: a novel link with autophagy

2012

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The Sonic Hegdehog/GLI (SHH/GLI) pathway has been extensively studied for its role in developmental and cancer biology. During early embryonic development the SHH pathway is involved mainly in pattern formation, while in latter stages its function in stem cell and progenitor proliferation becomes increasingly relevant. During postnatal development and in adult tissues, SHH/GLI promotes cell homeostasis by actively regulating gene transcription, recapitulating the function observed during normal tissue growth. In this review, we will briefl y discuss the fundamental importance of SHH/GLI in tumor growth and cancer evolution and we will then provide insights into a possible novel mechanism of SHH action in cancer through autophagy modulation in cancer stem cells. Autophagy is a homeostatic mechanism that when disrupted can promote and accelerate tumor progression in both cancer cells and the stroma that harbors tumorigenesis. Understanding possible new targets for SHH signaling and its contribution to cancer through modulation of autophagy might provide better strategies in order to design combined treatments and perform clinical trials.

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“…The deregulation of the HH pathway represses the retinoblastoma tumor suppressor-gene (Rb) and induces expression of the proto-onco gene N-myc , a key transcription factor which is overexpressed in malignant glioma cells [13]. Recent studies with cyclopamine, a Sonic hedgehog (SHH) inhibitor, have highlighted the importance of HH signals for growth and survival of CSC [14, 15]. Importantly, the HH signal has the potential to instruct the quiescent GSC to enter into the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling sensitizes Glioma stem cells to endogenous nano-irradiation

et al. 2014

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The existence of therapy resistant glioma stem cells is responsible for the high recurrence rate and incurability of glioblastomas. The Hedgehog pathway activity plays an essential role for self-renewal capacity and survival of glioma stem cells. We examined the potential of the Sonic hedgehog ligand for sensitizing of glioma stem cells to endogenous nano-irradiation. We demonstrate that the Sonic hedgehog ligand preferentially and efficiently activats glioma stem cells to enter the radiation sensitive G2/M phase. Concomitant inhibition of de novo thymidine synthesis with fluorodeoxyuridine and treatment with the Auger electron emitting thymidine analogue 5-[I-125]-Iodo-4′-thio-2′-deoxyuridine ([I-125]ITdU) leads to a fatal nano-irradiation in sensitized glioma stem cells. Targeting of proliferating glioma stem cells with DNA-incorporated [I-125]ITdU efficiently invokes the intrinsic apoptotic pathway despite active DNA repair mechanisms. Further, [I-125]ITdU completely inhibits survival of glioma stem cells in vitro. Analysis of non-stem glioblastoma cells and normal human astrocytes reveals that glioma stem cells differentially respond to Sonic hedgehog ligand. These data demonstrate a highly efficient and controllable single-cell kill therapeutic model for targeting glioma stem cells.

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Inhibition of the sonic hedgehog pathway by cyplopamine reduces the CD133+/CD15+ cell compartment and the in vitro tumorigenic capability of neuroblastoma cells

Cited by 34 publications

References 21 publications

GAS1 induces cell death through an intrinsic apoptotic pathway

GAS1 induces cell death through an intrinsic apoptotic pathway

Sonic Hedgehog in cancer stem cells: a novel link with autophagy

Hedgehog signaling sensitizes Glioma stem cells to endogenous nano-irradiation

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