Oncogenic pathways impinging on the G2-restriction point

Foijer, Floris; Simonis, Marieke; Vliet, Martin van; Wessels, Lodewyk; Kerkhoven, Ron; Sorger, Peter K.; Riele, Hein te

doi:10.1038/sj.onc.1210724

Cited by 8 publications

(7 citation statements)

References 39 publications

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“…The level of cyclin D1 which promotes progression through G1/S phases was elevated, while cyclin B1, promoting G2/M transition, was barely present [45,46]. According with previous studies [47,48] the cyclins pro le was consistent with G2-arrest. However, broblasts seem to be long-term arrested rather than irreversible senescence since after treatment removal cells resumed proliferation even in case of prolonged exposure to Onco-P20 (Fig.…”

Section: Results Effect Of Onco D-p20 Treatment On Cell Proliferation supporting

confidence: 55%

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel-Hyaluronan Bioconjugate: in vitro Evaluation in Non-Melanoma Skin Cancer

Bellei

Caputo

Migliano

et al. 2020

Preprint

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Abstract Background: Cancers are complex organs which encompass not only the tumor cells but also cells within the surrounding stroma. Such cells, mainly cancer associated fibroblasts (CAFs) and immune infiltrating cells, facilitate many aspects of cancer development providing a structural and supportive framework rich of bioactive compounds. So far, there are emerging studies proposing the combination of conventional anti-cancer therapy, directed against neoplastic cells, to molecules targeting tumor microenviroment. Methods: The study was designed to evaluated the pharmacological properties of the anti-tumor agent paclitaxel conjugated to hyaluronic acid (HA) on non-melanoma skin cancer (NMSC) and on the surronding dermal fibroblasts. This molecule, named Oncofid-P20 (Onco-P20), targets preferentially cells expressing high level of CD44, the natural ligand of HA.Results: Consistent with paclitaxel’s mechanism of action involving interferences with the normal breackdown of microtubules during cell division, highly sensible carcinoma cells underwent rapidly to apoptotic cell death. Interestingly, less sensible cells such as dermal fibroblasts resisted to the Onco-P20 treatment and experirenced a senescent-like status characterized by morphological change, decreaded proliferation, and significant modification of the gene espression profile. Onco-P20-treated fibroblasts lowered growth factors production, down-modulate Wnt signal pathway and acquired a pro-inflammatory profile. Independently to the direct exposure to taxol, in presence of Onco-P20-treated fibroblasts or their conditioned medium, carcinoma cells reduced the proliferation rate. Similar to NHF, fibroblasts isolated from skin cancer tumor lesion or from tissue adjacent to the tumor acquired an anti-neoplastic activity under Oncofid-P20 treatment.Conclusion: Collectively, our data demonstrated that Onco-P20, exerting both a direct and a NHF-mediated indirect paracrine effect on carcinoma cells, is a good candidate for an innovative therapy alternative to surgery for treatment of NMSC.

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Section: Results Effect Of Onco D-p20 Treatment On Cell Proliferation supporting

confidence: 55%

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel-Hyaluronan Bioconjugate: in vitro Evaluation in Non-Melanoma Skin Cancer

Bellei

Caputo

Migliano

et al. 2020

Preprint

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“…MAPKs have an important role in the G 2 /M transition. Recently, it has been shown that changes in the expression of c-Myc, Fos and DUSPs were associated with G 2 cell cycle arrest and re-entry into mitosis [48]. However the role of MAPKs signalling pathways on the G 2 /M arrest is not yet well understood.…”

Section: Discussionmentioning

confidence: 99%

“…Both activation and inhibition of the ERK pathway have been associated with the G 2 /M delay [44 -47], and preincubation of cells with ERKs specific inhibitors not always abolishes the G 2 /M arrest [49,50] implying that progression through the G 2 /M phase is a complex process and that other pathways may be implicated. It has been shown that the PI3K/Akt may also contribute to the G 2 /M transition [48,49]. Further studies are needed to determine whether the response of Caco-2 cells to EA and urolithins involves the modulation of additional pathways.…”

Section: Discussionmentioning

confidence: 99%

Gene expression, cell cycle arrest and MAPK signalling regulation in Caco‐2 cells exposed to ellagic acid and its metabolites, urolithins

González‐Sarrías

Espı́n

Tomás-Barberán

et al. 2009

Molecular Nutrition Food Res

144

105

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Novel gene expression profiles and cellular functions modulated in Caco-2 cells in response to the dietary polyphenol, ellagic acid (EA), and its colonic metabolites, urolithin-A (3,8-dihydroxy-6H-dibenzo[b,d] pyran-6-one) and urolithin-B (3-hydroxy-6H-dibenzo[b,d] pyran-6-one) have been identified. Exposure of cells to EA and urolithins arrested cell growth at the S- and G(2)/M-phases. Transcriptional profiling using microarray and functional analysis revealed changes in the expression levels of MAPK signalling genes such as, growth factor receptors (FGFR2, EGFR), oncogenes (K-Ras, c-Myc), and tumour suppressors (DUSP6, Fos) and of genes involved in cell cycle (CCNB1, CCNB1IP1). Results suggest that EA and urolithin-A and -B, at concentrations achievable in the lumen from the diet, might contribute to colon cancer prevention by modulating the expression of multiple genes in epithelial cells lining the colon. Some of these genes are involved in key cellular processes associated with cancer development and are currently being investigated as potential chemopreventive targets.

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“…Inhibition of checkpoint effector pathways by caffeine has been shown to increase sensitization to DNA damaging agents leading to cell death in several cell lines [39;40]. A recent report indicates that both the overexpression of c-MYC and the activating mutation of RAS were able to override the G2-restriction point in serum-starved mouse embryonic fibroblasts; however c-MYC overexpression resulted in increased apoptosis, whereas RAS activation resulted in continued proliferation in the absence of serum [41]. Studies by Knauf et al, demonstrated that expression of HRAS V12 in rat thyroid PCCL3 cells accelerated cell cycle progression after ionizing radiation, corresponding to an increase in chromosomal instability [42;43].…”

Section: Discussionmentioning

confidence: 99%

Bypass of hexavalent chromium-induced growth arrest by a protein tyrosine phosphatase inhibitor: Enhanced survival and mutagenesis

Bae

Camilli

Chun

et al. 2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Although the consequences of genotoxic injury include cell cycle arrest and apoptosis, cell survival responses after genotoxic injury can produce intrinsic death-resistance and contribute to the development of a transformed phenotype. Protein tyrosine phosphatases (PTPs) are integral components of key survival pathways, and are responsible for their inactivation, while PTP inhibition is are often associated with enhanced cell proliferation. Our aim was to elucidate signaling events that modulate cell survival after genotoxin exposure. Diploid human lung fibroblasts (HLF) were treated with Cr(VI) (as Na 2 CrO 4 ), the soluble oxyanionic dissolution product of certain particulate chromates, which are well-documented human respiratory carcinogens. In vitro soluble Cr(VI) induces a wide spectrum of DNA damage, in both the presence and absence of a broad-range PTP inhibitor, sodium orthovanadate (SOV). Notably, SOV abrogated Cr(VI)-induced clonogenic lethality. The enhanced survival of Cr(VI)-exposed cells after SOV treatment was predominantly due to a bypass of cell cycle arrest, as there was no effect of the PTP inhibitor on Cr-induced apoptosis. Moreover, the SOV effect was not due to decreased Cr uptake as evidenced by unchanged Cr-DNA adduct burden. Additionally, the bypass of Cr-induced growth arrest by SOV was accompanied by a decrease in Cr(VI)-induced expression of cell cycle inhibiting genes, and an increase in Cr(VI)-induced expression of cell cycle promoting genes. Importantly, SOV resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of certain types of DNA damage may lead to increased genomic instability, via bypass of cell cycle checkpoints.

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Oncogenic pathways impinging on the G2-restriction point

Cited by 8 publications

References 39 publications

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel-Hyaluronan Bioconjugate: in vitro Evaluation in Non-Melanoma Skin Cancer

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel-Hyaluronan Bioconjugate: in vitro Evaluation in Non-Melanoma Skin Cancer

Gene expression, cell cycle arrest and MAPK signalling regulation in Caco‐2 cells exposed to ellagic acid and its metabolites, urolithins

Bypass of hexavalent chromium-induced growth arrest by a protein tyrosine phosphatase inhibitor: Enhanced survival and mutagenesis

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