DNp73 Exerts Function in Metastasis Initiation by Disconnecting the Inhibitory Role of EPLIN on IGF1R-AKT/STAT3 Signaling

Steder, Marc; Alla, Vijay; Meier, Claudia; Spitschak, Alf; Pahnke, Jens; Fürst, Katharina; Kowtharapu, Bhavani S.; Engelmann, David; Petigk, Janine; Egberts, Friederike; Schäd‐Trcka, Susanne; Gross, Gerd; Nettelbeck, Dirk M.; Niemetz, Annett; Pützer, Brigitte M.

doi:10.1016/j.ccr.2013.08.023

Cited by 84 publications

(99 citation statements)

References 42 publications

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“…These DNp73 functions are in agreement with recent data indicating that DNp73 drives migration and invasion of non-metastatic melanoma cells facilitating the epithelialmesenchymal transition phenotype of these cells. 55 It has become increasingly clear that tumor vessel abnormalities contribute to create a microenvironment that facilitates tumor progression. Therefore, it is highly relevant to identify novel molecules involved in angiogenesis and to integrate them in the molecular networks that orchestrate vascular morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

et al. 2015

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Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-β and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.

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Section: Discussionmentioning

confidence: 99%

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

et al. 2015

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“…Numerous studies have provided substantial evidence that DNp73 bestows chemoresistance by decreasing intracellular drug accumulation through upregulation of the ABC transporters A2, A5, and B1 (2,3). Moreover, we recently demonstrated that the DNp73 variant DEx2/3p73 causes dramatic increases in cancer malignancy via promoting the transition from an epithelial to a highly motile mesenchymal (EMT) phenotype, leading to increased invasiveness and metastases formation in xenograft mouse models (4). DNp73-mediated acquisition of mesenchymal properties involves interference with wild-type TAp73-dependent transactivation of LIMA1/EPLIN that consecutively fosters activation of the IGF1R-AKT-Slug signaling and downregulation of E-cadherin.…”

Section: Introductionmentioning

confidence: 99%

“…H1299 and A549 lung cancer cells obtained from the ATCC, and HEK293T (BioCat, Heidelberg, Germany) are tested and authenticated by short tandem repeat analysis (in 2015). Cells were cultured as described previously (4). For inhibitor studies, cells were exposed to IGF1R Inhibitor II (Merck; 30 mmol/L) or antisense-oligonucleotide ASO116 gapmer (4, 7).…”

Section: Cell Culture and Antisense Oligonucleotide Transfectionmentioning

confidence: 99%

p73 and IGF1R Regulate Emergence of Aggressive Cancer Stem–like Features via miR-885-5p Control

et al. 2016

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Cancer stem-like cells (CSC) have been proposed to promote cancer progression by initiating tumor growth at distant sites, suggesting that stem-like cell features can support metastatic efficiency. Here, we demonstrate that oncogenic DNp73, a dominant-negative variant of the tumor-suppressor p73, confers cancer cells with enhanced stem-like properties. DNp73 overexpression in noninvasive melanoma and lung cancer cells increased anchorage-independent growth and elevated the expression of the pluripotency factors CD133, Nanog, and Oct4. Conversely, DNp73 depletion in metastatic cells downregulated stemness genes, attenuated sphere formation and reduced the tumor-initiating capability of spheroids in tumor xenograft models. Mechanistic investigations indicated that DNp73 acted by attenuating expression of miR-885-5p, a direct regulator of the IGF1 receptor (IGF1R) responsible for stemness marker expression. Modulating this pathway was sufficient to enhance chemosensitivity, overcoming DNp73-mediated drug resistance. Clinically, we established a correlation between low p73 function and high IGF1R/CD133/ Nanog/Oct4 levels in melanoma specimens that associated with reduced patient survival. Our work shows how DNp73 promotes cancer stem-like features and provides a mechanistic rationale to target the DNp73-IGF1R cascade as a therapeutic strategy to eradicate CSC. Cancer Res; 76(2); 197-205. Ó2015 AACR.

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“…In melanoma, both isoforms of p63 (TAp63 and DeltaNp63) negatively regulate apoptosis through ameliorating expression of Bcl-2 through translocation to the mitochondria and preventing nuclear p53 stabilization in response to genotoxic stress [60]. In case of p73, DeltaNp73 is considered as an oncoprotein since the expression of DeltaNp73 is linked to progression and metastasis in melanoma [61,62]. In contrast, TAp73 plays a role of tumour suppressive role in melanoma.…”

Section: Preventing Other Mechanisms From Inactivating P53mentioning

confidence: 99%

Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy

2014

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a b s t r a c tThe tumour suppressor p53 is a master sensor of stress and it controls the expression of hundreds to thousands of genes with diverse biological functions including cell cycle arrest, apoptosis, and senescence. Consequently p53 is the most mutated gene found in human cancer and p53 mutation rate varies from 5% to 95%. Importantly p53 activity is often inactivated in tumours expressing structurally wild type p53. Thus one of the major challenges in cancer research is to restore the tumour suppressive function of p53. Intensive studies in the past decade have demonstrated that in addition to mutation, p53 activities are largely regulated by cellular factors that control the expression level and/or transcriptional activities of p53. MDM2, MDM4, p14ARF and the ASPP family of proteins are among the most studied regulators of p53. With increased understanding of the complexity of p53 regulation, various p53 reactivating approaches are being developed. This review will focus on the recent understanding of p53 inactivation in melanoma and the approaches to reactivate p53 in preclinical studies. Recent success in the therapeutic targeting of the BRAFV600E oncogenic protein was accompanied with subsequent relapse caused by acquired drug resistance.Restoration of the tumour suppressive function of p53 presents a parallel cancer therapeutic opportunity alongside BRAFV600E inhibition. Thus targeted therapy and concurrent reactivation of p53 may be a fertile ground to achieve synergistic killing of the 50% of cancer cells that express structurally wild type p53.

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DNp73 Exerts Function in Metastasis Initiation by Disconnecting the Inhibitory Role of EPLIN on IGF1R-AKT/STAT3 Signaling

Cited by 84 publications

References 42 publications

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

p73 and IGF1R Regulate Emergence of Aggressive Cancer Stem–like Features via miR-885-5p Control

Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy

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