Expression of mTOR signaling pathway markers in prostate cancer progression

Kremer, Celeste L.; Klein, Russell D.; Mendelson, Jenny; Browne, Walden; Samadzedeh, Linda K.; Vanpatten, Kristie A.; Highstrom, Lindsey; Pestano, Gary A.; Nagle, Raymond B.

doi:10.1002/pros.20410

Cited by 166 publications

(140 citation statements)

References 36 publications

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“…Other authors have reported similar results in breast carcinomas, melanomas and prostate cancer (5)(6)(7)(8). In a study on breast cancer, phosphorylation of AKT, mTOR and 4E-BP1 was associated with tumor development and progression (7).…”

Section: Introductionsupporting

confidence: 52%

“…Transfer of 4E-BP1 phosphorylation site mutants into breast carcinoma cells suppresses their tumorigenicity (9). Kremer et al (8) investigated the expression patterns of several biomarkers of the mTOR pathway in prostate cancer and observed that 4E-BP1 levels, in combination with mTOR and PTEN activation, were among the best biomarkers of prostate intraepithelial neoplasia (PIN). Other reports have associated p-4E-BP1 with patient survival in prostate cancer (5) and melanoma (6).…”

Section: Introductionmentioning

confidence: 99%

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The effect of p-4E-BP1 and p-eIF4E on cell proliferation in a breast cancer model

Cajal¹

2011

Int J Oncol

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Abstract. Cell signaling pathways and protein translation are crucial for understanding malignant transformation. 4E-BP1 and the eIF4F complex regulate cap-dependent translation. We investigated how 4E-BP1 and eIF4E phosphorylation status affects in vitro and in vivo cell proliferation in a breast cancer model. Cells from 2 breast carcinoma lines (MDA-MB 231 and MDA-MB 468) and human fibroblasts (IMR90 cells) were infected in vitro with a retrovirus carrying a wild-type 4E-BP1 or a mutant 4E-BP1 unable to hyperphosphorylate. Overexpression of the mutant 4E-BP1 induced a significant decrease in cell proliferation in IMR90 and MDA-MB 468 cells, but not in MDA-MB 231 cells. A correlation was observed between baseline-phosphorylated eIF4E (p-eIF4E) levels and sensitivity to 4E-BP1 transduction. By co-immunoprecipitation, p-eIF4E seemed to present lower affinity for 4E-BP1 than total eIF4E in MDA-MB 468 cells. After treatment with CGP57380, the MAP kinase-interacting kinase (MNK) inhibitor, downregulation of p-eIF4E levels was associated with an increase of E-cadherin and β-catenin protein expression. These results provide evidence that 4E-BP1 transduction leads to a decrease in cell proliferation, and that high p-eIF4E levels may counteract the suppressor effect of 4E-BP1. We propose that high p-4E-BP1 and p-eIF4E levels are central factors in cell signaling and reflect the oncogenic potential of cell signaling pathways in breast cancer.

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Section: Introductionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

The effect of p-4E-BP1 and p-eIF4E on cell proliferation in a breast cancer model

Cajal¹

2011

Int J Oncol

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“…However, we found an association of the expression of these proteins with the proliferation index, which in the novel grading scheme for GEP-NET is the central classifier for tumour grade. mTOR expression and activity have been evaluated in a broad variety of human tumours, including most of the major tumour types, namely endometrial (Darb-Esfahani et al 2009), esophageal (Boone et al 2008), renal (Campbell et al 2008), colorectal (Tampellini et al 2007), prostate (Kremer et al 2006), liver (Sahin et al 2004), breast (Zhou et al 2004, Rojo et al 2007, lung (Anagnostou et al 2009) and ovarian (Noske et al 2008) cancer as well as glioblastoma (Pelloski et al 2006). In all tumour entities, mTOR was either upregulated and/or activated in the tumour tissue when compared with the Figure 5 Correlation of mTOR, 4EBP1, p-4EBP1, p-S6K and p-eIF4E expression with survival in stage IV midgut NET.…”

Section: Discussionmentioning

confidence: 99%

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Kasajima¹,

Pavel²,

Darb‐Esfahani³

et al. 2010

Endocrine Related Cancer

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Clinical trials indicate efficacy of drugs inhibiting the mammalian target of rapamycin (mTOR) in the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NET); however, information on detailed expression and activity patterns of mTOR in these tumours is sparse. We investigated the expression of mTOR and expression as well as phosphorylation of its downstream targets 4EBP1, S6K and eIF4E in a cohort of 99 human GEP-NET by immunohistochemistry. We correlated our findings with clinicopathological variables and patient prognosis. We found that 61, 93, 80, 69, 57 and 79% of GEP-NET were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1), nuclear p-4EBP1, phospho-S6K (p-S6K) and phospho-eIF4E (p-eIF4E) respectively. mTOR expression and activity were higher in foregut than in midgut tumours. In foregut tumours, expression of mTOR was higher when distant metastases were present (PZ0.035). Strong mTOR activity was associated with higher proliferative capacity. In patients with stage IV midgut tumours, strong p-S6K expression was associated with poor disease-specific survival (PZ0.048). In conclusion, mTOR shows considerable variations in expression and activity patterns in GEP-NET in dependence of tumour location and metastatic status. We hypothesise that these differences in mTOR expression and activity might possibly influence response to mTOR inhibitors.

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“…mTOR and other upstream proteins, such as phosphatidylinositol 3-kinase and Akt, have been implicated in the proliferation, differentiation, and malignant transformation in prostate cancer progression (20). mTOR activates ribosomal p70S6K and eukaryotic initiation factor EIF-4E and therefore translation.…”

Section: Introductionmentioning

confidence: 99%

Synergistic effect of a novel antiandrogen, VN/124-1, and signal transduction inhibitors in prostate cancer progression to hormone independence in vitro

Schayowitz

Sabnis

Njar

et al. 2008

Molecular Cancer Therapeutics

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This study was carried out to determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer. We investigated the role of the androgen receptor and its relationship to other signal transduction proteins. A hormone-refractory prostate cancer cell line [high-passage LNCaP (HP-LNCaP)] was established in vitro. Cells were treated with inhibitors of mammalian target of rapamycin and tyrosine kinase receptors. Expression of these proteins and the androgen receptor were measured by Western immunoblotting. Analysis of the model and various treatments was also assessed through proliferation assays, luciferase activation assays, binding assays, and ELISA. Our novel antiandrogen, VN/124-1, effectively inhibited proliferation of hormone-resistant prostate cancer cell lines (HP-LNCaP), which were no longer sensitive to bicalutamide and had increased expression of the androgen receptor. Treatment with everolimus or gefitinib resulted in an increase in protein expression and activation of the androgen receptor. Conversely, inhibition of the androgen receptor resulted in increased expression of IGFR1B, pHER2, pmTOR, and pAkt. The addition of bicalutamide to everolimus or gefitinib inhibited cell proliferation in HP-LNCaP cells. However, the addition of VN/124-1 has proven to be superior to bicalutamide, and the combination was synergistic (P < 0.05) compared with either agent alone. This study suggests that compensatory cross-talk between the androgen receptor and various signaling pathways may account for decreased sensitivity to androgen receptor antagonists and the progression to hormone-resistant prostate cancer. Furthermore, these findings suggest that inhibition of both pathways may provide effective control in hormone-resistant prostate cancer and restore sensitivity to androgen antagonists in hormone-refractory patients.

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Expression of mTOR signaling pathway markers in prostate cancer progression

Abstract: Results suggest that 4E-BP1 overexpression is strongly associated with prostate cancer, especially when combined with PTEN and mTOR expression data. Hierarchical clustering analysis utilizing PTEN, mTOR, and 4E-BP1 separated normal from cancer cell populations in most cases.

Cited by 166 publications

References 36 publications

The effect of p-4E-BP1 and p-eIF4E on cell proliferation in a breast cancer model

The effect of p-4E-BP1 and p-eIF4E on cell proliferation in a breast cancer model

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Synergistic effect of a novel antiandrogen, VN/124-1, and signal transduction inhibitors in prostate cancer progression to hormone independence in vitro

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