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1.
Clin Cancer Res ; 15(8): 2872-8, 2009 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-19336517

RESUMEN

PURPOSE: Both phosphatidylinositol 3-kinase/AKT and RAS/mitogen-activated protein kinase signal transduction pathways mediate 4E-BP1 phosphorylation, releasing 4E-BP1 from the mRNA cap and permitting translation initiation. Given the prevalence of PTEN and BRAF mutations in melanoma, we first examined translation initiation, as measured by phosphorylated 4E-BP1 (p-4E-BP1), in metastatic melanoma tissues and cell lines. We then tested the association between amounts of total and p-4E-BP1 and patient survival. EXPERIMENTAL DESIGN: Seven human metastatic melanoma cells lines and 72 metastatic melanoma patients with accessible metastatic tumor tissues and extended follow-up information were studied. Expression of 4E-BP1 transcript, total 4E-BP1 protein, and p-4E-BP1 was examined. The relationship between 4E-BP1 transcript and protein expression was assessed in a subset of patient tumors (n = 41). The association between total and p-4E-BP1 levels and survival was examined in the larger cohort of patients (n = 72). RESULTS: 4E-BP1 was hyperphosphorylated in 4 of 7 melanoma cell lines harboring both BRAF and PTEN mutations compared with untransformed melanocytes or RAS/RAF/PTEN wild-type melanoma cells. 4E-BP1 transcript correlated with 4E-BP1 total protein levels as measured by the semiquantitative reverse-phase protein array (P = 0.012). High levels of p-4E-BP1 were associated with worse overall and post-recurrence survival (P = 0.02 and 0.0003, respectively). CONCLUSION: Our data show that translation initiation is a common event in human metastatic melanoma and correlates with worse prognosis. Therefore, effective inhibition of the pathways responsible for 4E-BP1 phosphorylation should be considered to improve the treatment outcome of metastatic melanoma patients.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Melanoma/mortalidad , Melanoma/patología , Fosfoproteínas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Ciclo Celular , Línea Celular Tumoral , Femenino , Humanos , Masculino , Melanoma/metabolismo , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Fosfoproteínas/genética , Fosforilación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo
2.
FEBS Lett ; 580(24): 5647-52, 2006 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-16996503

RESUMEN

Estrogen, which has been strongly implicated in breast cancer, suppresses apoptosis in estrogen receptor (ER) positive MCF-7 breast cancer cells. Phospholipase D (PLD), which is commonly elevated in ER negative breast cancer cells, also suppresses apoptosis. Survival signals generated by both estrogen and PLD are dependent upon elevated Myc expression. We report here that estrogen- and PLD-induced increases in Myc expression are due to reduced turnover of Myc protein. Estrogen and PLD suppressed phosphorylation of Myc at Thr58--a site that targets Myc for degradation by the proteasome. The data provide a mechanism for elevated Myc expression in hormone-dependent and hormone-independent breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Estrógenos/metabolismo , Fosfolipasa D/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Línea Celular Tumoral , Estradiol/farmacología , Regulación Neoplásica de la Expresión Génica , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Fosfolipasa D/genética , Fosforilación/efectos de los fármacos , Fosfoserina/metabolismo , Fosfotreonina/metabolismo , Unión Proteica
3.
J Biol Chem ; 281(23): 15862-8, 2006 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-16595654

RESUMEN

MDA-MB-231 human breast cancer cells belong to a highly invasive metastatic cell line that depends on phospholipase D (PLD) activity for survival when deprived of serum growth factors. In response to the stress of serum withdrawal, there is a rapid and dramatic increase in PLD activity. Concomitant with increased PLD activity, there was an increase in the ability of MDA-MB-231 cells to both migrate and invade Matrigel. The ability of MDA-MB-231 cells to both migrate and invade Matrigel was dependent on both PLD and mTOR, a downstream target of PLD signals. Serum withdrawal also led to a PLD-dependent increase in the expression of the stress factor, hypoxia-inducible factor-1alpha. These data reveal that PLD survival signals not only prevent apoptosis but also stimulate cell migration and invasion, linking the ability to suppress apoptosis with the ability to metastasize.


Asunto(s)
Movimiento Celular , Supervivencia Celular , Estrés Oxidativo , Fosfolipasa D/metabolismo , Línea Celular Tumoral , Medio de Cultivo Libre de Suero , Humanos , Metástasis de la Neoplasia
4.
J Biol Chem ; 280(43): 35829-35, 2005 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-16109716

RESUMEN

A critical aspect of tumor progression is the generation of survival signals that overcome default apoptotic programs. Recent studies have revealed that elevated phospholipase D activity generates survival signals in breast and perhaps other human cancers. We report here that the elevated phospholipase D activity in the human breast cancer cell line MDA-MB-231 suppresses the activity of the putative tumor suppressor protein phosphatase 2A in a mammalian target of rapamycin (mTOR)-dependent manner. Increasing the phospholipase D activity in MCF7 cells also suppressed protein phosphatase 2A activity. Elevated phospholipase D activity suppressed association of protein phosphatase 2A with both ribosomal subunit S6-kinase and eukaryotic initiation factor 4E-binding protein 1. Suppression of protein phosphatase 2A by SV40 small t-antigen has been reported to be critical for the transformation of human cells with SV40 early region genes. Consistent with a critical role for protein phosphatase 2A in phospholipase D survival signals, either SV40 small t-antigen or pharmacological suppression of protein phosphatase 2A restored survival signals lost by the suppression of either phospholipase D or mTOR. Blocking phospholipase D signals also led to reduced phosphorylation of the pro-apoptotic protein BAD at the protein phosphatase 2A dephosphorylation site at Ser-112. The ability of phospholipase D to suppress protein phosphatase 2A identifies a critical target of an emerging phospholipase D/mTOR survival pathway in the transformation of human cells.


Asunto(s)
Neoplasias de la Mama/patología , Fosfolipasa D/metabolismo , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Proteínas Quinasas/fisiología , Proteínas Adaptadoras Transductoras de Señales , Antígenos Transformadores de Poliomavirus/metabolismo , Apoptosis , Western Blotting , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular , Línea Celular Tumoral , Supervivencia Celular , Humanos , Inmunoprecipitación , Modelos Biológicos , Mutación , Fosfolipasa D/química , Fosfoproteínas/metabolismo , Fosforilación , Proteínas Quinasas/metabolismo , Proteína Fosfatasa 2 , ARN Interferente Pequeño/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Ribosomas/enzimología , Serina/química , Serina-Treonina Quinasas TOR
5.
Mol Cell Biol ; 25(17): 7917-25, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16107734

RESUMEN

Estrogens, which have been strongly implicated in the development of breast cancer, enhance proliferation of mammary epithelial cells and, importantly, estrogen receptor (ER)-positive breast cancer cells. In the absence of serum growth factors, the ER-positive MCF-7 breast cancer cell line undergoes apoptosis. Estrogens, most commonly 17-beta-estradiol (E2), can suppress apoptosis in MCF-7 cells deprived of serum. While E2 stimulated a short-term transient increase in Myc expression, E2 stimulated a sustained increase in Myc expression that was detectable at 48 h and pronounced at 5 days, the point where increased proliferation of MCF-7 cells in the absence of serum could be detected. The delayed increase in Myc expression was not dependent upon transcription of the Myc gene. Suppression of Myc expression reversed the survival effects of E2. The Myc-dependent survival signal generated by E2 was dependent upon basal levels of mTOR (mammalian target of rapamycin) and two upstream regulators of mTOR, phosphatidylinositol 3-kinase and phospholipase D (PLD). Stable elevated expression of PLD2 also increased Myc expression and provided a Myc-dependent survival signal in the absence of E2. These data provide evidence that E2 promotes survival signals in breast cancer cells through an mTOR-dependent increase in Myc expression. The data also suggest that elevated PLD expression, which is common in breast cancer, confers E2 independence.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Estrógenos/farmacología , Fosfolipasa D/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Estradiol/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfolipasa D/genética , Fosforilación , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Proteínas Proto-Oncogénicas c-myc/genética , Suero , Serina-Treonina Quinasas TOR
6.
Oncogene ; 24(4): 672-9, 2005 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-15580312

RESUMEN

Cancer cells generate survival signals to suppress default apoptotic programs that protect from cancer. Phosphatidylinositol-3-kinase (PI3K) generates a survival signal that is frequently dysregulated in human cancers. Phospholipase D (PLD) has also been implicated in signals that promote survival. One of the targets of PLD signaling is mTOR (mammalian target of rapamycin), a critical regulator of cell cycle progression and cell growth. We report here that elevated PLD activity in the MDA-MB-231 human breast cancer cell line generates an mTOR-dependent survival signal that is independent of PI3K. In contrast, MDA-MB-435S breast cancer cells, which have very low levels of PLD activity, are dependent on PI3K for survival signals. The data presented here identify an alternative survival signal that is dependent on PLD and mTOR and is active in a breast cancer cell line where the PI3K survival pathway is not active.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Fosfolipasa D/metabolismo , Proteínas Quinasas/metabolismo , Transducción de Señal , Neoplasias de la Mama/genética , Línea Celular Tumoral , Supervivencia Celular , Medio de Cultivo Libre de Suero/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosfolipasa D/genética , Inhibidores de Proteínas Quinasas/farmacología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR
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