Specific Peptide Ligand for Grb7 Signal Transduction Protein and Pancreatic Cancer Metastasis

Tanaka, Shinji; Pero, Stephanie C.; Taguchi, Kenichi; Shimada, Mitsuo; Mori, Masaki; Krag, David N.; Arii, Shigeki

doi:10.1093/jnci/djj105

Cited by 81 publications

(138 citation statements)

References 35 publications

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“…We have shown previously that the G7-18NATE peptide inhibits the association of Grb7 with the ErbB family of tyrosine kinases (Pero et al, 2002) and focal adhesion kinase (Tanaka et al, 2006). The signal transduction pathway for Grb7 has not been identified clearly.…”

Section: Discussionmentioning

confidence: 97%

“…Combining chemotherapy with molecules, such as our Grb7 peptide, may have great potential at effectively killing the cancer cells and minimising toxicity. In our recent study we have shown that the Grb7 peptide inhibitor had low toxicity in mice (Tanaka et al, 2006). In addition, this peptide is non-phosphorylated, which may have an advantage of stability of other SH2 targeting peptides that possess a highly charged phosphate group.…”

Section: Discussionmentioning

confidence: 98%

“…The free peptide was synthesised as a redox stable thioether-bridged analog, referred to as G7-18NATE (Pero et al, 2002). G7-18NATE was found to specifically bind to the SH2 domain of Grb7 and inhibit the association of Grb7 protein with various RTKs (Pero et al, 2002;Tanaka et al, 2006). Since Grb7 is an intracellular target, we made G7-18NATE peptide cell permeable by adding the penetratin peptide sequence, referred to as G7-18NATE-P. Penetratin is a peptide derived from the Drosophila transcription factor Antennapedia that mediates rapid cellular delivery of proteins and peptides (Deshayes et al, 2005).…”

mentioning

confidence: 99%

“…Since Grb7 is an intracellular target, we made G7-18NATE peptide cell permeable by adding the penetratin peptide sequence, referred to as G7-18NATE-P. Penetratin is a peptide derived from the Drosophila transcription factor Antennapedia that mediates rapid cellular delivery of proteins and peptides (Deshayes et al, 2005). We have shown previously that the cell permeable G7-18NATE-P peptide is able to successfully translocate across the cell membrane and significantly inhibited cell migration and peritoneal metastasis in a pancreatic cancer mouse model (Tanaka et al, 2006). In the present study we also tested G7-18NATE conjugated to the Tat cell penetrating peptide.…”

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confidence: 99%

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Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

et al. 2007

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Grb7 has potential importance in the progression of cancer. We have previously identified a novel peptide that binds to the SH2 domain of Grb7 and inhibits its association with several different receptor tyrosine kinases. We have synthesised the Grb7 peptide, G7-18NATE, with two different cell penetrating peptides, Penetratin and Tat. In this study, we have shown that both Penetratin-and Tat-conjugated G7-18NATE peptides are able to inhibit the proliferation of SK-BR-3, ZR-75-30, MDA-MB-361 and MDA-MB-231 breast cancer cells. There was no significant effects on breast cancer MCF-7cells, non-malignant MCF 10A or 3T3 cells. In addition, there was no significant inhibition of proliferation by Penetratin or Tat alone or by their conjugates with arbitrary peptide sequence in any of the cell lines tested. We determined the EC 50 of G7-18NATE-P peptide for SK-BR-3 cell proliferation to be 7.663 Â 10 À6 M. Co-treatment of G7-18NATE-P peptide plus Doxorubicin in SK-BR-3 breast cancer cells resulted in an additional inhibition of proliferation, resulting in 56 and 84% decreases in the Doxorubicin EC 50 value in the presence of 5 Â 10 À6 and 1.0 Â 10 À5 M G7-18NATE-P peptide, respectively. Importantly, the co-treatment with Doxorubicin and the delivery peptide did not change the Doxorubicin EC 50 . Since Grb7 associates with ErbB2, we assessed whether the peptide inhibitor would have a combined effect with a molecule that targets ErbB2, Herceptin. Co-treatment of Herceptin plus 1.0 Â 10 À5 M G7-18NATE-P peptide in SK-BR-3 cells resulted in a 46% decrease in the Herceptin EC 50 value and no decrease following the co-treatment with Herceptin and penetratin alone. This Grb7 peptide has potential to be developed as a therapeutic agent alone, in combination with traditional chemotherapy, or in combination with other targeting molecules.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

et al. 2007

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“…In this clinical study, protein expression of Grb7 was not significantly correlated with tumor size. It was reported that the Grb7 peptide inhibitor significantly attenuated cell migration in vitro and peritoneal metastasis in a mouse model of pancreatic cancer cells, but the proliferation of pancreatic cells treated with the Grb7 peptide inhibitor was not significantly different from that of untreated cells (20). These data suggested that Grb7 protein played an important role in cell invasion of HCC cells, but might not contribute to cell proliferation.…”

Section: Discussionmentioning

confidence: 84%

Role of Growth Factor Receptor–Bound Protein 7 in Hepatocellular Carcinoma

Itoh

Taketomi

Tanaka

et al. 2007

Molecular Cancer Research

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The human growth factor receptor -bound protein 7 (Grb7) is an adaptor molecule and is related to cell invasion. In this present study, we investigated the clinical and biological significance of Grb7 expression in human hepatocellular carcinoma (HCC). We reviewed 64 consecutive patients who had undergone liver resection for HCC, and we investigated the correlation between Grb7 expression and clinical outcome. To analyze the biological behavior of Grb7 in vitro and in vivo, we established Grb7 stable knockdown HCC cells using RNA interference technology. The positive staining of Grb7 protein was correlated with portal venous invasion (P < 0.01), hepatic venous invasion (P < 0.01), and intrahepatic metastasis (P < 0.05). Positive expression of Grb7 was significantly correlated with focal adhesion kinase (FAK) protein levels in HCC (P < 0.01). The Grb7-and FAK-positive group showed a significantly poorer prognosis as compared with the Grb7-and FAK-negative group (P < 0.05). Grb7 knockdown HCC cells exhibited significantly lower levels of invasion potential (P < 0.05) and motility (P < 0.05) than the control cells in vitro; moreover, Grb7 knockdown HCC cells showed delayed onset of the tumors compared with the control cells in vivo. Grb7 expression can modulate the invasive phenotype of HCC. Grb7 plays an important role in HCC progression and is strongly associated with expression of FAK. Grb7 could be a therapeutic target in HCC.

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Precision medicine based on surgical oncology in the era of genome‐scale analysis and genome editing technology

Tanaka

2018

Annals of Gastroent Surgery

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Accumulated evidence suggests that multiple molecular and cellular interactions promote cancer evolution in vivo. Surgical oncology is of growing significance to a comprehensive understanding of the malignant diseases for therapeutic application. We have analyzed more than 1000 clinical samples from surgically resected tissue to identify molecular biomarkers and therapeutic targets for advanced malignancies. Cancer stemness and mitotic instability were then determined as the essential predictors of aggressive phenotype with poor prognosis. Recently, whole genome/exome sequencing showed a mutational landscape underlying phenotype heterogeneity in caners. In addition, integrated genomic, epigenomic, transcriptomic, metabolic, proteomic and phenomic analyses elucidated several molecular subtypes that cluster in liver, pancreatic, biliary, esophageal and gastroenterological cancers. Identification of each molecular subtype is expected to realize the precise medicine targeting subtype‐specific molecules; however, there are obstacle limitations to determine matching druggable targets or synthetic lethal interactions. Current breakthroughs in genome editing technology can provide us with unprecedented opportunity to recapitulate subtype‐specific pathophysiology in vitro and in vivo. Given a great potential, on‐demand editing system can design actionable strategy and revolutionize precision cancer medicine based on surgical oncology.

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Specific Peptide Ligand for Grb7 Signal Transduction Protein and Pancreatic Cancer Metastasis

Abstract: The Grb7 peptide inhibitor appears to be a promising molecularly targeted therapeutic agent against metastatic pancreatic cancer.

Cited by 81 publications

References 35 publications

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells

Role of Growth Factor Receptor–Bound Protein 7 in Hepatocellular Carcinoma

Precision medicine based on surgical oncology in the era of genome‐scale analysis and genome editing technology

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