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1.
Sci Rep ; 8(1): 3947, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29500400

RESUMO

Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either in-vitro or in-vivo in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although PTEN loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy.


Assuntos
Divisão Celular , Fase G2 , Recombinação Homóloga , PTEN Fosfo-Hidrolase/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/terapia , Quinase 1 do Ponto de Checagem/genética , Terapia Combinada , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Resultado do Tratamento
2.
BMC Cancer ; 15: 963, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26672755

RESUMO

BACKGROUND: Deletions of chromosome 10q23, including the PTEN (phosphatase and tensin homolog) locus, are known to occur in breast cancer, but systematic analyses of its clinical relevance are lacking. METHODS: We thus analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using a PTEN-specific probe. RESULTS: PTEN deletions were detected in 19% of no special type, 9% of lobular, 4% of tubular cancers and 46% in carcinomas with medullary features. 98.7% of deletions were heterozygous and only 1.3% were homozygous. PTEN deletion was significantly linked to advanced tumor stage (p=0.0054), high-grade (p<0.0001), high tumor cell proliferation (Ki67 Labeling Index; p<0.0001), and shortened overall survival (p=0.0090). PTEN deletions were inversely associated with features of luminal type breast cancers (ER/PR positivity; p<0.0001 each, and CCND1 amplification; p=0.0020). PTEN deletions were also strongly linked to amplification of genes involved in the PTEN/AKT pathway such as MYC (p=0.0430) and HER2 (p=0.0065). Remarkably the combined analysis of MYC, HER2, CCND1 and PTEN aberrations suggested that aberrations of multiple PTEN/AKT pathway genes have a strong additive effect on breast cancer prognosis. While cancers with one of these aberrations behaved only marginally different from cancers with none, disease outcome was markedly worse in cancers with two or more aberrations as compared to those with only one aberration (p=0.0002). In addition, the particularly poor prognosis of patients with HER2 amplification and PTEN deletions challenges the concept of PTEN deletions interfering with trastuzumab therapy. CONCLUSION: PTEN deletion occurs in a relevant fraction of breast cancers, and is linked to aggressive tumor behavior. Reduced PTEN function cooperates with MYC and HER2 activation in conferring aggressive phenotype to cancer cells.


Assuntos
Neoplasias da Mama/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Deleção Cromossômica , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Prognóstico , Análise Serial de Tecidos
3.
Biochem Biophys Res Commun ; 260(3): 724-8, 1999 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-10403833

RESUMO

The cytoplasmatic domain of the beta-subunit of the human IGF-1 receptor (residues 929-1337) has been overexpressed in insect cells using the baculovirus expression system. Synthesis of the soluble protein (IGFK, M(r) 46 kDa) in Spodoptera frugiperda (Sf9) cells was detected 24 h after infection and maximal accumulation was achieved 40-48 h postinfection. Rapid purification to near homogeneity (>/=95% pure protein) was accomplished by sequential chromatography on Resource-Q and phenyl-Sepharose with a specific activity of 142 nmol/min/mg using poly[Glu:Tyr] as substrate. The purified IGFK showed a preference for Mn(2+) ions and a linear incorporation of (32)P from [gamma-(32)P]ATP over a 20-fold dilution of the protein and was stimulated 20-fold by the polycation poly-L-lysine. Interestingly, the kinase autophosphorylated on tyrosine and serine residues. In contrast, a kinase-negative mutant, IGFK-K1003A, did not undergo phosphorylation on tyrosine or serine residues, respectively, suggesting that IGF-1 receptor kinase is a dual specific kinase.


Assuntos
Fragmentos de Peptídeos/metabolismo , Receptor IGF Tipo 1/metabolismo , Trifosfato de Adenosina/metabolismo , Substituição de Aminoácidos , Animais , Baculoviridae/genética , Linhagem Celular , Citosol/enzimologia , Citosol/metabolismo , Humanos , Cinética , Magnésio/farmacologia , Manganês/farmacologia , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/isolamento & purificação , Fosforilação , Polilisina/farmacologia , Receptor IGF Tipo 1/química , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/isolamento & purificação , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Serina/metabolismo , Solubilidade , Spodoptera , Fatores de Tempo , Tirosina/metabolismo
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