Selective ablation of Notch3 in HCC enhances doxorubicin’s death promoting effect by a p53 dependent mechanism

Giovannini, Catia; Gramantieri, Laura; Chieco, Pasquale; Minguzzi, Manuela; Lago, F.; Pianetti, Simona; Ramazzotti, E.; Marcu, Kenneth B.; Bolondi, Luigi

doi:10.1016/j.jhep.2008.12.032

Cited by 84 publications

(85 citation statements)

References 28 publications

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“…A double negative feedback loop was also found in case of the cross talk with P53 pathway. It was found that the phosphorylated P53 inhibits NUC_NICD1/2/3/4 for its further transcription; on the other hand the phosphorylation of P53 is blocked by NICD1/2/3/4 in cytoplasm [63,65,[80][81][82]. We assume that this double negative feedback loop helps to maintain the Notch pathway activation or inhibition under several pathological conditions and acts as a "Switch" for the production of Notch target proteins in cells.…”

Section: Feedback Loopsmentioning

confidence: 89%

“…On the other hand there are also some inhibitor molecules or complex, such as, Co-repressor complex (COR), HDAC, SMRT and the phosphorylated form of P53 (inhibitors of NUC_NICD1/2/3/4), which also have significant number of OutDegree values in the network. Interestingly, only HIF1A and NRARP from the output molecules of this network had significant Out-Degree and Total-Degree values, which were occurring because of the presence of feedback loops of these proteins in the network ( Figure S2 and Figure S3 in Supplementary file, for Out-Degree and Total Degree values) [63,65,[80][81][82]85].…”

Section: Computational Study Of Reconstructed Notch Signaling Pathwaymentioning

confidence: 97%

“…Cross talks with other pathways: Notch pathway has cross connections with different signaling pathways such as, JAK/STAT, PTEN/PI3K/AKT, RAS/MAPK, TGFB/SMAD3, CYCLIN/CDK, HYPOXIA/HIF1A, BCL2/IAP/ ANTI-APOPTOSIS, P65/P50/NFKB etc., which widen the scope of the study [10,17,22,24,44,64,65,[79][80][81][82][83][84]. In our reconstructed Notch pathway (Figure 1), we tried to include more number of cross talks events with core proteins of Notch pathway.…”

Section: Reactions In Nucleusmentioning

confidence: 99%

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Drug Targets and Biomarker Identification from Computational Study of Human Notch Signaling Pathway

Chowdhury¹,

Sarkar²

2013

Clin Exp Pharmacol

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Notch signaling pathway is widely implicated in controlling various cellular functions, cell fate determination, and stem cell renewal in human but aberrant activity in cancer stem cells may cause different types of cancers. Understanding the complexity of this pathway to identify important targets for cancer therapy and to suppress the pathway activity without affecting the normal functions is of utmost importance to clinical and experimental pharmacologists. For developing therapeutic strategy, non availability of detailed molecular interactions, complex regulations and cross talks with other pathways pose a serious challenge to get a coherent understanding of this pathway. This motivated us to reconstruct the largest human cell specific Notch pathway with more number of molecules and interactions available from literatures and databases. To identify probable drug targets and biomarkers for cancer prognosis, we also performed computational study of the pathway using structural and logical analysis and identified important hub proteins, cross talks and feedback mechanisms. The model simulation is validated using reported mRNA expression profile in Glioblastoma cell line and the predictions not only show significant accuracy but also able to identify the undetermined expressions. From our simulation, to identify novel combinations of drug targetable proteins and better substitute for GAMMA SECRETASE inhibition, we proposed two alternative scenarios: partial suppression of Notch target proteins by NICD1 & HIF1A; and complete suppression by NICD1 & MAML, in Glioblastoma cell line. This reconstructed Notch signaling pathway and the computational analysis for identifying new biomarkers and combinatory drug targets will be useful for future in-vitro and in-vivo analysis to control different cancers.

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Section: Feedback Loopsmentioning

confidence: 89%

Section: Computational Study Of Reconstructed Notch Signaling Pathwaymentioning

confidence: 97%

Section: Reactions In Nucleusmentioning

confidence: 99%

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Drug Targets and Biomarker Identification from Computational Study of Human Notch Signaling Pathway

Chowdhury¹,

Sarkar²

2013

Clin Exp Pharmacol

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“…It was found that the Notch ligand Delta-1 can inhibit apoptosis by reducing the cleavage of PARP-1 (17). Selective ablation of Notch3 in hepatocellular carcinoma enhances the doxorubicin death promoting effect (18). The inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation (19).…”

Section: Discussionmentioning

confidence: 99%

Akt-mTOR signaling is involved in Notch-1-mediated glioma cell survival and proliferation

Zheng¹

2010

Oncol Rep

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Abstract. Both Notch signaling and Akt-mTOR signaling pathway are involved in glioma cell proliferation and survival. Previous studies have shown that Notch-1 is overexpressed in many glioma cell lines and primary human gliomas. Blocking of Notch signaling pathway can induces glioma cell apoptosis and growth suppression. However, the underlying molecular mechanism is not clear. We report that activation of the Notch pathway by intracellular domain of human Notch-1 (NIC-1) strongly activates Akt and promotes U251 glioma cell proliferation. Knockdown of Notch-1 by RNA interference suppresses Akt activation, reduces glioma cell growth rate and induce cell apoptosis. Following Notch-1 suppression, phosphorylated Akt and its downstream effector mTOR were reduced. Knockdown of Notch-1 also involves downregulation of anti-apoptotic protein MCL-1, in parallel with activation of apoptotic associate proteins PARP, caspase-9 and caspase-3. Our data demonstrate that Notch-1 can positively regulate Akt-mTOR pathways, which is associated with glioma cell proliferation and apoptosis. This also suggests a molecular mechanism for the inhibitory effect of Notch-1 RNA interference on glioma cell proliferation through Akt-mTOR signaling pathway.

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“…[41,68] On the other hand, there is evidence that Notch is oncogenic in nature. [69][70][71] As time passes, growing evidence may indicate that although individual HCC signatures may include Notch as a tumor suppressor, the majority of HCC Notch mediation is through overexpression and oncogenic activation. For instance, Villanueva et al [72] revealed that the conditional expression of NICD1 in a mouse model led to HCC in all test subjects within the 1st year.…”

Section: Targeting Notch In Hepatocellular Carcinomamentioning

confidence: 99%

Notch signaling in hepatocellular carcinoma: molecular targeting in an advanced disease

Sokolowski¹,

Balamurugan²,

Kunnimalaiyaan³

et al. 2015

Hepatoma Res

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The use of alternative therapeutic approaches in advanced carcinogenesis is a growing investigative base. One such cancer, primary liver cancer, is one of the most commonly occurring cancers worldwide and often presents in late stage disease consequently preventing traditional curative modalities. As a result, hepatocellular carcinoma (HCC), representing the majority of primary liver cancer, is the third most common cause of cancer-related deaths globally. Survival rates are linked to stage of presentation as well as concomitant cirrhosis limiting the 5-year survival in these patients to < 20%. Alternative strategies are in dire need as patients in this cohort have limited palliative options. Currently, sorafenib is the only approved systemic therapy; however, it has a limited survival advantage and low effi cacy prompting the empirical need for further evaluation. Understanding of cancer therapy has led to an enhanced focus on the Notch pathway as a potential target for advanced HCC. Notch signaling is a critical component of development and cell fate and has been linked to various modalities including liver regeneration and as a key driver in carcinogenesis. In this review, we will provide a review of the current status of the Notch signaling in liver cancer and of Notch as an alternative potential strategy for advanced HCC.

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Selective ablation of Notch3 in HCC enhances doxorubicin’s death promoting effect by a p53 dependent mechanism

Cited by 84 publications

References 28 publications

Drug Targets and Biomarker Identification from Computational Study of Human Notch Signaling Pathway

Drug Targets and Biomarker Identification from Computational Study of Human Notch Signaling Pathway

Akt-mTOR signaling is involved in Notch-1-mediated glioma cell survival and proliferation

Notch signaling in hepatocellular carcinoma: molecular targeting in an advanced disease

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