Pancreatic Cancer Cell Proliferation Is Phosphatidylinositol 3-Kinase Dependent

Perugini, Richard A.; McDade, Theodore P.; Vittimberga, Frank J.; Callery, Mark P.

doi:10.1006/jsre.2000.5833

Cited by 89 publications

(69 citation statements)

References 18 publications

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“…*P ¼ o0.05 treated with control siRNA and those treated with siCEACAM6. Activation of the serine/threonine kinase Akt is common in pancreatic adenocarcinoma (Semba et al, 2003), and is an important determinant of pancreatic adenocarcinoma cellular proliferation (Perugini et al, 2000). Inhibition of the phosphoinositide-3-OH kinase/ Akt pathway impairs anchorage-independent growth in PANC1 pancreatic adenocarcinoma cells (Yao et al, 2002), and expression of constitutively active Akt has been shown to block epithelial cell anoikis (Khwaja et al, 1997).…”

Section: Anoikis Resistance Correlates With In Vivo Metastatic Abilitymentioning

confidence: 99%

RETRACTED ARTICLE: CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells

et al. 2004

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Anoikis is the apoptotic response induced in normal cells by inadequate or inappropriate adhesion to substrate. It is postulated that resistance to anoikis facilitates tumorigenesis and metastasis. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an immunoglobulin superfamily member overexpressed in a number of human cancers and implicated in anoikis resistance. We tested the effect of CEACAM6 gene silencing on anoikis in pancreatic adenocarcinoma cell lines. Anoikis was induced in PANC1, Capan2, MiaPaCa2 and Mia AR (a MiaPaCa2-derived anoikis-resistant subline) by culture in poly-2-hydroxyethylmethacrylate-coated wells. Anoikis was quantified by YO-PRO-1/propidium iodide staining and flow cytometry. The role of caspase activation was determined using fluorometric profiling and the caspase inhibitor Z-Val-Ala-Asp-fluoromethyl ketone (Z-VADfmk). CEACAM6 expression was suppressed by RNA interference. Using a nude mouse orthotopic xenograft model, we assessed the effect of this treatment on in vivo metastatic ability. Anoikis resistance was associated with increased CEACAM6 expression. CEACAM6-specific short interfering ribonucleic acid (siRNA), but not control siRNA, increased susceptibility to caspase-mediated anoikis, an effect abrogated by Z-VAD-fmk, and decreased Akt phosphorylation (Ser-473) under anchorage-independent conditions. CEACAM6 gene silencing reversed the acquired anoikis resistance of Mia AR and inhibited its in vivo metastatic ability. CEACAM6 warrants further investigation as a novel therapeutic target for the treatment of pancreatic adenocarcinoma.

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Section: Anoikis Resistance Correlates With In Vivo Metastatic Abilitymentioning

confidence: 99%

RETRACTED ARTICLE: CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells

et al. 2004

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“…To date, the only active chemotherapy agent, gemcitabine (2V,2V-difluorodeoxycytidine), has an objective response rate of <20% (2). Several studies as well as our own have previously shown that perturbation to the frequently up-regulated phosphoinositide 3-kinase-protein kinase B (PI3K-PKB) cell survival pathway in pancreatic cancer confers therapeutic benefits (3)(4)(5). Inhibition of PI3K led to decreased proliferation and increased apoptosis in pancreatic cancer in vitro and in vivo (5).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies as well as our own have previously shown that perturbation to the frequently up-regulated phosphoinositide 3-kinase-protein kinase B (PI3K-PKB) cell survival pathway in pancreatic cancer confers therapeutic benefits (3)(4)(5). Inhibition of PI3K led to decreased proliferation and increased apoptosis in pancreatic cancer in vitro and in vivo (5). In addition, combining PI3K or PKB inhibitors with cytotoxic drugs resulted in the reversal of drug resistance in pancreatic cancer cells and orthotopic xenografts (3)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of PI3K led to decreased proliferation and increased apoptosis in pancreatic cancer in vitro and in vivo (5). In addition, combining PI3K or PKB inhibitors with cytotoxic drugs resulted in the reversal of drug resistance in pancreatic cancer cells and orthotopic xenografts (3)(4)(5)(6)(7). Therefore, altering molecular targets pharmacologically in the PI3K-PKB pathway has proven to be a fruitful approach for improving the therapeutic index in pancreatic cancer models.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Integrin-Linked Kinase by a Selective Small Molecule Inhibitor, QLT0254, Inhibits the PI3K/PKB/mTOR, Stat3, and FKHR Pathways and Tumor Growth, and Enhances Gemcitabine-Induced Apoptosis in Human Orthotopic Primary Pancreatic Cancer Xenografts

Yau

Wheeler²,

Sutton³

et al. 2005

Cancer Research

122

104

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Integrin-linked kinase (ILK) couples integrins and growth factors to downstream signaling pathways involving phosphatidylinositol 3-kinase, protein kinase B/Akt (PKB/Akt), and glycogen synthase kinase-3B. The anticancer effects of ILK inhibitor QLT0254 were tested in an orthotopic primary xenograft model of pancreatic cancer. The pharmacodynamic effects of a single dose of QLT0254 on the phosphorylation of PKB/Akt were measured by immunohistochemistry and Western blotting, and showed a decrease of >80% after 2 hours, followed by recovery over 24 hours, consistent with the pharmacokinetic profile of this compound in mice. There was also suppression in phosphorylated PKB Thr 308 , forkhead in rhabdomyosarcoma, S6K1, S6, 4E-BP1, and signal transducers and activators of transcription 3 Tyr 705 and Ser 727 protein levels with ILK inhibition by QLT0254. However, we did not observe an effect on phosphoinositide-dependent kinase 1, glycogen synthase kinase-3B, and extracellular signal-regulated kinase phosphorylation or on total PKB and ILK protein expression levels with QLT0254 treatment. In tumor growth inhibition experiments, daily treatment with QLT0254 for 3 weeks was well tolerated and produced significant tumor growth inhibition compared with vehicle control (P = 0.001). When a single dose of QLT0254 and chemotherapy agent gemcitabine was administered, there was a significant 5.4-fold increase in acute apoptosis in the combination therapy group compared with vehicle controls (P = 0.002). However, the acute effects of QLT0254 on proliferation were not statistically significant. These results show in vivo evidence that ILK plays a prominent role in oncogenic phosphatidylinositol 3-kinase/PKB signaling in vivo with major impact on the mammalian target of rapamycin, signal transducers and activators of transcription 3, and forkhead in rhadomyosarcoma signaling pathways, suggesting that ILK inhibitors might show activity in pancreatic cancer patients. (Cancer Res 2005; 65(4): 1497-1504

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“…These data come from the available cell lines, though no data are available on the incidence of AKT activation in human tumours. Recent reports have demonstrated that the AKT pathway is a potent survival signal in these pancreatic cancer cell lines, as inhibition of PI3K, the upstream activator of AKT, has been shown to sensitise these cells to the apoptotic effect of chemotherapy in vitro (Ng et al, 2000;Perugini et al, 2000;Yao et al, 2002). Furthermore, using these cell lines in animal studies, inhibition of PI3K was well tolerated and increased the efficacy of chemotherapy in vivo (Ng et al, 2000;Bondar et al, 2002).…”

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confidence: 99%

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

et al. 2003

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When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P ¼ 0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P ¼ 0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.

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Pancreatic Cancer Cell Proliferation Is Phosphatidylinositol 3-Kinase Dependent

Cited by 89 publications

References 18 publications

RETRACTED ARTICLE: CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells

RETRACTED ARTICLE: CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells

Inhibition of Integrin-Linked Kinase by a Selective Small Molecule Inhibitor, QLT0254, Inhibits the PI3K/PKB/mTOR, Stat3, and FKHR Pathways and Tumor Growth, and Enhances Gemcitabine-Induced Apoptosis in Human Orthotopic Primary Pancreatic Cancer Xenografts

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

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