RNA interference targeting focal adhesion kinase enhances pancreatic adenocarcinoma gemcitabine chemosensitivity

Duxbury, Mark; Ito, Hiromichi; Benoît, Éric; Zinner, Michael J.; Ashley, Stanley W.; Whang, Edward E.

doi:10.1016/j.bbrc.2003.10.060

Cited by 121 publications

(89 citation statements)

References 26 publications

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“…The results of the present study are along the lines of several other reports demonstrating that tumour mRNA expression of RRM1 was correlated with clinical response to gemcitabine/ cisplatin in stage IV NSCLC (Rosell et al, 2003(Rosell et al, , 2004Ceppi et al, 2006). In addition, inhibition of RRM2 mRNA expression in vitro with the use of interference RNA enhanced chemosensitivity of pancreatic adenocarcinomas to gemcitabine (Duxbury et al, 2003(Duxbury et al, , 2004. Apart from the well-known role of RRM2 in maintaining DNA integrity, several studies have reported that RRM2 has additional functions that influence the invasive phenotype.…”

Section: Discussionsupporting

confidence: 88%

Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine

et al. 2008

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Ribonucleotide reductase subunits M1 (RRM1) and M2 (RRM2) are involved in the metabolism of gemcitabine (2 0 ,2 0 -difluorodeoxycytidine), which is used for the treatment of nonsmall cell lung cancer. The mRNA expression of RRM1 and RRM2 in tumours from lung adenocarcinoma patients treated with docetaxel/gemcitabine was assessed and the results correlated with clinical outcome. RMM1 and RMM2 mRNA levels were determined by quantitative real-time PCR in primary tumours of previously untreated patients with advanced lung adenocarcinoma who were subsequently treated with docetaxel/gemcitabine. Amplification was successful in 42 (79%) of 53 enrolled patients. Low levels of RRM2 mRNA were associated with response to treatment (Po 0.001). Patients with the lowest expression levels of RRM1 had a significantly longer time to progression (P ¼ 0.044) and overall survival (P ¼ 0.02) than patients with the highest levels. Patients with low levels of both RRM1 and RRM2 had a significantly higher response rate (60 vs 14.2%; P ¼ 0.049), time to progression (9.9 vs 2.3 months; P ¼ 0.003) and overall survival (15.4 vs 3.6; P ¼ 0.031) than patients with high levels of both RRM1 and RRM2. Ribonucleotide reductase subunit M1 and RRM2 mRNA expression in lung adenocarcinoma tumours is associated with clinical outcome to docetaxel/gemcitabine. Prospective studies are warranted to evaluate the role of these markers in tailoring chemotherapy.

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Section: Discussionsupporting

confidence: 88%

Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine

et al. 2008

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“…FAK represents an important point of convergence for a variety of signaling cascades and has been shown to be tyrosine-phosphorylated and activated by Src kinases (49 -52). Levels of FAK activity, which depend on FAK tyrosine phosphorylation status, correlate with a variety of aspects of pancreatic adenocarcinoma malignant cellular behavior (37,38). FAK Tyr-397 is a potential high affinity binding site for the SH2 domain of c-Src, and FAK Tyr-397 phosphorylation leads to the recruitment of SH2-containing proteins such as Src family kinases (51,53).…”

Section: Discussionmentioning

confidence: 99%

“…FAK Focal Adhesion Kinase-FAK is an important substrate of c-Src and forms a central point in a variety of signaling cascades of importance in determining the malignant phenotype (37,38). Following treatment with either anti-CEACAM6 antibody or irrelevant IgG (followed by secondary antibody), cell lysates were prepared and FAK phosphorylation was quantified by immunoblotting for phosphorylation at Tyr-925, a c-Src phosphorylation site required for Grb SH2/SH3 adaptor protein binding (39).…”

Section: Ceacam6 Antibody Cross-linking Induces C-src-dependent Tyrosmentioning

confidence: 99%

CEACAM6 Cross-linking Induces Caveolin-1-dependent, Src-mediated Focal Adhesion Kinase Phosphorylation in BxPC3 Pancreatic Adenocarcinoma Cells

Duxbury

Ito

Ashley

et al. 2004

Journal of Biological Chemistry

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Despite lacking transmembrane or intracellular domains, glycosylphosphatidylinositol-anchored proteins can modulate intracellular signaling events, in many cases through aggregation within membrane "lipid raft" microdomains. CEACAM6 is a glycosylphosphatidylinositol-linked cell surface protein of importance in the anchorage-independent survival and metastasis of pancreatic adenocarcinoma cells. We examined the effects of antibody-mediated cross-linking of CEACAM6 on intracellular signaling events and anchorage-independent survival of the CEACAM6-overexpressing pancreatic ductal adenocarcinoma cell line, BxPC3. CEACAM6 cross-linking increased c-Src activation and induced tyrosine phosphorylation of p125 FAK focal adhesion kinase. Focal adhesion kinase phosphorylation was dependent on c-Src kinase activation, for which caveolin-1 was required. CEACAM6 cross-linking induced a significant increase in cellular resistance to anoikis. These observations represent the first characterization of the mechanism through which this important cell surface oncoprotein influences intracellular signaling events and hence malignant cellular behavior. CEACAM61 is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein that is overexpressed in a variety of human malignancies, including pancreatic adenocarcinoma (1, 2). This immunoglobulin superfamily member is emerging as an important determinant of a variety of aspects of the malignant cellular phenotype (1-3). We reported previously that levels of CEACAM6 expression modulate the susceptibility of pancreatic adenocarcinoma cells to anoikis (2). Normal epithelial cells require anchorage to an extracellular matrix for growth, survival, and differentiation. Resistance to anoikis, a subset of apoptosis induced by inadequate or inappropriate cell-substrate contact in normal cells, is a property of transformed cells that is associated with enhanced tumorigenesis and metastatic ability. Despite clear indications of its important role in cancer cell biology, the mechanisms through which CEACAM6 influences intracellular signal transduction remain poorly understood.Despite lacking transmembrane and intracellular domains, several GPI-anchored proteins, including CEACAM family members, are able to influence intracellular events and have been implicated in transmembrane signaling via tyrosine kinases (4 -7). GPI-anchored proteins are known to exist in clusters and form microdomains at the surface of the plasma membrane, referred to as "lipid rafts" (8). These microdomains appear to be important for GPI-anchored protein signal transduction. A number of signal transduction components, including Src family tyrosine kinases, are associated with lipid rafts, and cross-linking of cell surface molecules by a variety of techniques has proven to be a useful tool for exploring the functional roles of raft-associated proteins (9 -14).Here, we examine the effects of antibody-mediated crosslinking of CEACAM6 in pancreatic adenocarcinoma cells. We determine the effects of CEACAM6 cross-linking on ...

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“…Therefore, new strategies, such as combination with other drugs or a molecular approach, which allows the selection of responders, are necessary, in order to improve patient outcome. Several molecules including ABCC5 (49), c-Src (50), BNIP3 (51) and focal adhesion kinase (FAS) (52) have been reported to be a gemcitabine sensitive/resistance marker.…”

Section: Discussionmentioning

confidence: 99%

Ribonucleotide reductase subunit M1 assessed by quantitative double-fluorescence immunohistochemistry predicts the efficacy of gemcitabine in biliary tract carcinoma

Nakamura

Kohya²,

Kai³

et al. 2010

Int J Oncol

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Abstract. Gemcitabine is a commonly used chemotherapeutic agent for advanced biliary tract carcinoma (BTC), although its efficacy is insufficient. Therefore, it is essential to establish new diagnostic methods, which can predict responders before the treatment. The aim of this study is to identify the most reliable chemoresistance marker to gemcitabine in BTC among the 4 molecules (hENT1, dCK, RRM1 and RRM2) involved in gemcitabine metabolism. The expression of 4 molecules were investigated in 5 BTC cell lines, and correlated with gemcitabine sensitivity. RRM1 protein was also assessed by quantitative double-fluorescence immunohistochemistry (qDFIHC) in 10 patients with unresectable or recurrent BTC who received gemcitabine-based chemotherapy. RRM1 and RRM2 protein strongly correlated with the IC 50 value for gemcitabine in BTC cell lines (R=0.935, 0.771, respectively). In addition, patients with low RRM1 were significantly more sensitive to gemcitabine (p=0.033), and their survival was significantly better than patients with high RRM1 (p=0.001).In conclusion, RRM1 particularly in protein level is a reliable marker for gemcitabine resistance in BTC. Furthermore, qDFIHC is a useful method for the assessment of RRM1 protein, in order to design a tailor-made chemotherapeutic regimen for BTC patients.

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RNA interference targeting focal adhesion kinase enhances pancreatic adenocarcinoma gemcitabine chemosensitivity

Cited by 121 publications

References 26 publications

Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine

Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine

CEACAM6 Cross-linking Induces Caveolin-1-dependent, Src-mediated Focal Adhesion Kinase Phosphorylation in BxPC3 Pancreatic Adenocarcinoma Cells

Ribonucleotide reductase subunit M1 assessed by quantitative double-fluorescence immunohistochemistry predicts the efficacy of gemcitabine in biliary tract carcinoma

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