2005

DOI: 10.1016/j.lfs.2005.04.067

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Inhibition of Shc/Grb2 protein–protein interaction suppresses growth of B104-1-1 tumors xenografted in nude mice

Hyae-Kyeong Kim

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Moon‐Jin Jeong

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et al.

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Discussion4

Targeting the Grb2 Sh2 Domain1

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Cited by 11 publications

(7 citation statements)

References 23 publications

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“…The performed SH2 array uncovered Sck/Shc2 as a novel PAC member and signal transducer in PDAC. Interestingly, it was reported that blocking Shc/Grb2 interaction suppressed the growth of B104-1-1 tumours xenografted in nude mice, 37 showing that cancer treatment might also target the adapter proteins.…”

Section: Discussionmentioning

confidence: 99%

CD95 promotes metastatic spread via Sck in pancreatic ductal adenocarcinoma

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²

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et al. 2015

Cell Death Differ

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Cancer stem cells (CSCs) have been implicated in the initiation and maintenance of tumour growth as well as metastasis. Recent reports link stemness to epithelial–mesenchymal transition (EMT) in cancer. However, there is still little knowledge about the molecular markers of those events. In silico analysis of RNA profiles of 36 pancreatic ductal adenocarcinomas (PDAC) reveals an association of the expression of CD95 with EMT and stemness that was validated in CSCs isolated from PDAC surgical specimens. CD95 expression was also higher in metastatic pancreatic cells than in primary PDAC. Pharmacological inhibition of CD95 activity reduced PDAC growth and metastasis in CSC-derived xenografts and in a murine syngeneic model. On the mechanistic level, Sck was identified as a novel molecule indispensable for CD95's induction of cell cycle progression. This study uncovers CD95 as a marker of EMT and stemness in PDAC. It also addresses the molecular mechanism by which CD95 drives tumour growth and opens tantalizing therapeutic possibilities in PDAC.

“…The performed SH2 array uncovered Sck/Shc2 as a novel PAC member and signal transducer in PDAC. Interestingly, it was reported that blocking Shc/Grb2 interaction suppressed the growth of B104-1-1 tumours xenografted in nude mice, 37 showing that cancer treatment might also target the adapter proteins.…”

Section: Discussionmentioning

confidence: 99%

CD95 promotes metastatic spread via Sck in pancreatic ductal adenocarcinoma

¹

,

²

,

³

et al. 2015

Cell Death Differ

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Cancer stem cells (CSCs) have been implicated in the initiation and maintenance of tumour growth as well as metastasis. Recent reports link stemness to epithelial–mesenchymal transition (EMT) in cancer. However, there is still little knowledge about the molecular markers of those events. In silico analysis of RNA profiles of 36 pancreatic ductal adenocarcinomas (PDAC) reveals an association of the expression of CD95 with EMT and stemness that was validated in CSCs isolated from PDAC surgical specimens. CD95 expression was also higher in metastatic pancreatic cells than in primary PDAC. Pharmacological inhibition of CD95 activity reduced PDAC growth and metastasis in CSC-derived xenografts and in a murine syngeneic model. On the mechanistic level, Sck was identified as a novel molecule indispensable for CD95's induction of cell cycle progression. This study uncovers CD95 as a marker of EMT and stemness in PDAC. It also addresses the molecular mechanism by which CD95 drives tumour growth and opens tantalizing therapeutic possibilities in PDAC.

“…Therefore, Grb2 is essential for the Ras / Raf/ ERK pathway (35). Binding of the two SH3 domains of Grb2 to Sos homologue protein results in the activation of Ras.…”

Section: Discussionmentioning

confidence: 99%

Oridonin-Induced A431 Cell Apoptosis Partially Through Blockage of the Ras/Raf/ERK Signal Pathway

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et al. 2007

J Pharmacol Sci

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Abstract. We have reported that oridonin, a diterpenoid isolated from the plant Rabdosia rubescens, had apoptosis-inducing activities in many cell lines (e.g., human melanoma A375-S2, human cervical cancer HeLa, human breast adenocarcinoma MCF-7, and murine fibrosarcoma L929). In this study, we further investigated signaling events involved in oridonin-induced apoptosis in human epidermoid carcinoma A431 cells. It was found that the total tyrosine kinase activity was inhibited and the protein expressions of epidermal growth factor receptor (EGFR) and phosphorylated EGFR were decreased in oridonin-induced A431 cell apoptosis. Expression of EGFR downstream effector proteins, Grb2, Ras, Raf-1, and extracellular signal-regulated kinase (ERK), was also downregulated by oridonin. Moreover, the oridonin-induced apoptosis was augmented by the Ras inhibitor manumycin A, Raf-1 inhibitor GW5074, or ERK inhibitor PD98059, suggesting that inactivation of Ras, Raf, or ERK participates in oridonin-induced apoptosis. Taken together, oridonin-induced apoptosis in A431 cells might be through blocking EGFR and its downstream Ras / Raf/ ERK signal pathway.

“…SH2 domains are well-recognized pharmaceutical targets 86 . The concept that disruption of Grb2 SH2 domain interactions can significantly inhibit Grb2 signaling is supported by the effects of the general transcriptional inhibitor actinomycin D, which has been shown to block Grb2 SH2 domain interaction with Shc and tumor cell cycle progression [87][88][89] . Natural products and derivatives that block Grb2 SH2 domain binding interactions have also been characterized 90 .…”

Section: Targeting the Grb2 Sh2 Domainmentioning

confidence: 99%

Grb2 signaling in cell motility and cancer

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2008

Expert Opinion on Therapeutic Targets

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Metastasis is the primary cause of death in most human cancers, and understanding the molecular mechanisms underpinning this multistep process is fundamental to identifying novel molecular targets and developing more effective therapies. Growth Factor Receptor-bound protein 2 (Grb2) is a key molecule in intracellular signal transduction, linking activated cell surface receptors to downstream targets by binding to specific phosphotyrosine-containing and proline-rich sequence motifs. Grb2 signaling is critical for cell cycle progression and actin-based cell motility, and consequently, more complex processes such as epithelial morphogenesis, angiogenesis and vasculogenesis. These important functions make Grb2 a logical therapeutic target for strategies designed to prevent the spread of solid tumors through local invasion and metastasis. Here we review the role of Grb2 in cancer and specifically in metastasis-related processes, and summarize briefly the development of anti-cancer therapeutics selectively targeting this important adapter protein.

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