Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

Baritaki, Stavroula; Huerta-Yépez, Sara; Sahakyan, Anna; Karagiannides, Iordanis; Bakirtzi, Kyriaki; Jazirehi, Ali R.; Bonavida, Benjamin

doi:10.4161/cc.9.24.14229

Cited by 99 publications

(52 citation statements)

References 54 publications

(91 reference statements)

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“…MAPK signaling) can also drive EMT. Indeed, evidence for the induction of EMT through MAPK pathway activation of SNAI1 has been reported in other studies(38). In our model, MAPK signaling can drive EMT, independent of TGFβ (data not shown).…”

Section: Resultssupporting

confidence: 60%

Network Modeling of TGFβ Signaling in Hepatocellular Carcinoma Epithelial-to-Mesenchymal Transition Reveals Joint Sonic Hedgehog and Wnt Pathway Activation

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site, invade surrounding tissue, and establish distant metastases. A hallmark of EMT is the loss of E-cadherin expression, and one major signal for the induction of EMT is transforming growth factor beta (TGFβ, which is dysregulated in up to 40% of hepatocellular carcinoma (HCC). We have constructed an EMT network of 70 nodes and 135 edges by integrating the signaling pathways involved in developmental EMT and known dysregulations in invasive HCC. We then used discrete dynamic modeling to understand the dynamics of the EMT network driven by TGFβ. Our network model recapitulates known dysregulations during the induction of EMT and predicts the activation of the Wnt and Sonic hedgehog (SHH) signaling pathways during this process. We show, across multiple murine (P2E and P2M) and human HCC cell lines (Huh7, PLC/PRF/5, HLE, and HLF), that the TGFβ signaling axis is a conserved driver of mesenchymal phenotype HCC and confirm that Wnt and SHH signaling are induced in these cell lines. Furthermore, we identify by network analysis eight regulatory feedback motifs that stabilize the EMT process and show that these motifs involve cross-talk among multiple major pathways. Our model will be useful in identifying potential therapeutic targets for the suppression of EMT, invasion and metastasis in HCC.

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Section: Resultssupporting

confidence: 60%

Network Modeling of TGFβ Signaling in Hepatocellular Carcinoma Epithelial-to-Mesenchymal Transition Reveals Joint Sonic Hedgehog and Wnt Pathway Activation

et al. 2014

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“…Similar findings were observed following treatment with the proteasome inhibitor NPI-0052 or the NO donor DETANONOate. 129 The direct role of RKIP-induced expression in the inhibition of EMT was corroborated by several lines of evidence, namely, overexpression of RKIP, silencing Snail, and inhibition of NF-κB. In contrast, the induction of EMT was demonstrated by the inhibition of RKIP or the overexpression of Snail.…”

Section: Role Of Rkip In the Inhibition Of Drug-resistant Cells Wimentioning

confidence: 92%

RKIP-Mediated Chemo-Immunosensitization of Resistant Cancer Cells via Disruption of the NF-κB/Snail/YY1/RKIP Resistance-Driver Loop

Bonavida

2014

Crit Rev Oncog

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Cancer remains one of the most dreadful diseases. Whereas most treatment regimens for various cancers have resulted in improved clinical responses and sometimes cures, unfortunately, subsets of cancer patients are either pre-treatment resistant or develop resistance following therapy. These subsets of patients develop cross-resistance to unrelated therapeutics and usually succumb to death. Thus, delineating the underlying molecular mechanisms of resistance of various cancers and identifying molecular targets for intervention are the current main focus of research investigations. One approach to investigate cancer resistance has been to identify pathways that regulate resistance and develop means to disrupt these pathways in order to override resistance and sensitize the resistant cells to cell death. Hence, we have identified one pathway that is dysregulated in cancer, namely, the NF-κB/Snail/YY1/RKIP loop, that has been shown to regulate, in large part, tumor cell resistance to apoptosis by chemotherapeutic and immunotherapeutic cytotoxic drugs. The dysregulated resistant loop is manifested by the overexpression of NF-κB, Snail and YY1 activities and the underexpression of RKIP. The induction of RKIP expression results in the downregulation of NF-κB, Snail and YY1 and the sensitization of resistant cells to drug-induced apoptosis. These findings identified RKIP, in addition to its anti-proliferative and metastatic suppressor functions, as an anti-resistance factor. This brief review describes the role of RKIP in the regulation of drug sensitivity via disruption of the NF-κB/Snail/YY1/RKIP loop that regulates resistance in cancer cells.

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“…Activation of Snail, downstream of NF-κβ induces metastasis in part by repressing transcription of Raf-1 kinase inhibitor protein (RKIP). High levels of % NO have been shown to suppress EMT both in vitro and in vivo by inhibiting NF-κβ and Snail, thereby upregulating RKIP and E-cadherin protein levels (Baritaki et al, 2010). Modulation of this circuitry by % NO has also been shown to sensitize resistant tumor cells to apoptotic stimuli from chemotherapeutic agents (Bonavida & Baritaki, 2011).…”

Section: Epithelial-mesenchymal Transition and Metastasismentioning

confidence: 97%