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1.
Anticancer Res ; 42(6): 3217-3230, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35641277

RESUMO

BACKGROUND: Eight human catalytic phosphoinositide 3-kinase (PI3K) isoforms exist which are subdivided into three classes. While class I isoforms have been well-studied in cancer, little is known about the functions of class II PI3Ks. MATERIALS AND METHODS: The expression pattern and functions of the class II PI3KC2ß isoform were investigated in a panel of tumour samples and cell lines. RESULTS: Overexpression of PI3KC2ß was found in subsets of tumours and cell lines from acute myeloid leukemia (AML), glioblastoma multiforme (GBM), medulloblastoma (MB), neuroblastoma (NB), and small cell lung cancer (SCLC). Specific pharmacological inhibitors of PI3KC2ß or RNA interference impaired proliferation of a panel of human cancer cell lines and primary cultures. Inhibition of PI3KC2ß also induced apoptosis and sensitised the cancer cells to chemotherapeutic agents. CONCLUSION: Together, these data show that PI3KC2ß contributes to proliferation and survival in AML, brain tumours and neuroendocrine tumours, and may represent a novel target in these malignancies.


Assuntos
Neoplasias Encefálicas , Neoplasias Cerebelares , Leucemia Mieloide Aguda , Tumores Neuroendócrinos , Doença Aguda , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/genética , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Neoplasias Pulmonares , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Fosfatidilinositol 3-Quinases/metabolismo
2.
Clin Cancer Res ; 14(4): 1172-81, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18281552

RESUMO

PURPOSE: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in neuroblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in neuroblastoma. EXPERIMENTAL DESIGN: The expression pattern and functions of class I(A) PI3K isoforms were investigated in tumor samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110alpha or p110delta in SH-SY5Y and LA-N-1 cells by means of RNA interference. RESULTS: Overexpression of the catalytic p110delta and regulatory p85alpha isoforms was detected in a panel of primary neuroblastoma samples and cell lines, compared with normal adrenal gland tissue. Although down-regulation of either p110alpha or p110delta led to impaired cell growth, reduced expression of p110delta also had a selective effect on the survival of SH-SY5Y cells. Decreased levels of p110delta were found to induce apoptosis and lead to lower expression levels of antiapoptotic Bcl-2 family proteins. SH-SY5Y cells with decreased p110delta levels also displayed reduced activation of ribosomal protein S6 kinase in response to stimulation with epidermal growth factor and insulin-like growth factor-I. CONCLUSIONS: Together, our data reveal a novel function of p110delta in neuroblastoma growth and survival.


Assuntos
Proliferação de Células , Sobrevivência Celular/fisiologia , Neuroblastoma/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Apoptose/fisiologia , Western Blotting , Linhagem Celular Tumoral , Células Cultivadas , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Isoenzimas/metabolismo , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina-Treonina Quinases TOR
3.
Biochem J ; 406(1): 57-66, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17506723

RESUMO

AT/RTs (atypical teratoid/rhabdoid tumours) of the CNS (central nervous system) are childhood malignancies associated with poor survival rates due to resistance to conventional treatments such as chemotherapy. We characterized a panel of human AT/RT and MRT (malignant rhabdoid tumour) cell lines for expression of RTKs (receptor tyrosine kinases) and their involvement in tumour growth and survival. When compared with normal brain tissue, AT/RT cell lines overexpressed the IR (insulin receptor) and the IGFIR (insulin-like growth factor-I receptor). Moreover, insulin was secreted by AT/RT cells grown in serum-free medium. Insulin potently activated Akt (also called protein kinase B) in AT/RT cells, as compared with other growth factors, such as epidermal growth factor. Pharmacological inhibitors, neutralizing antibodies, or RNAi (RNA interference) targeting the IR impaired the growth of AT/RT cell lines and induced apoptosis. Inhibitors of the PI3K (phosphoinositide 3-kinase)/Akt pathway also impaired basal and insulin-stimulated AT/RT cell proliferation. Experiments using RNAi and isoform-specific pharmacological inhibitors established a key role for the class I(A) PI3K p110alpha isoform in AT/RT cell growth and insulin signalling. Taken together, our results reveal a novel role for autocrine signalling by insulin and the IR in growth and survival of malignant human CNS tumour cells via the PI3K/Akt pathway.


Assuntos
Comunicação Autócrina , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Substâncias de Crescimento/metabolismo , Insulina/metabolismo , Comunicação Autócrina/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Pré-Escolar , Proteínas Cromossômicas não Histona/metabolismo , Meios de Cultura Livres de Soro , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Ativação Enzimática/efeitos dos fármacos , Feminino , Substâncias de Crescimento/farmacologia , Humanos , Lactente , Insulina/farmacologia , Secreção de Insulina , Isoenzimas/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Proteína SMARCB1 , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo
4.
Crit Rev Oncol Hematol ; 63(3): 215-30, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17658267

RESUMO

Acute myeloid leukemia (AML) is a quickly progressing, heterogeneous clonal disorder of hematopoietic progenitor cells. Significant progress in understanding the pathogenesis of AML has been achieved in the past few years. Two major types of genetic events are thought to give rise to leukemic transformation: alterations in the activity of transcription factors controlling hematopoietic differentiation and activation of components of receptor tyrosine kinase (RTK) signaling pathways. This has led to the development of promising new therapeutic strategies for the disease. In this article, we will discuss recent developments in the field of molecularly targeted therapies for AML, which involve RTKs such as FMS-like tyrosine kinase 3 (Flt3), c-Kit and signal transduction via the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Initial results imply that targeting RTKs is a very promising approach for AML and that other receptors, such as the insulin-like growth factor receptor (IGF-IR), could also represent new targets in the future.


Assuntos
Leucemia Mieloide/tratamento farmacológico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Doença Aguda , Sistemas de Liberação de Medicamentos , Humanos , Transdução de Sinais/efeitos dos fármacos
5.
Drug News Perspect ; 19(5): 261-72, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16941048

RESUMO

As insulin-like growth factor (IGF) signaling has been recognized to play an important role in human cancer, the IGF-I receptor (IGF-IR) is currently the focus of intensive research aimed at developing novel antitumor agents. The IGF system is frequently deregulated in cancer cells by the establishment of autocrine loops involving IGF-I or -II and/or IGF-IR over-expression. Moreover, epidemiological studies have suggested a link between elevated IGF levels and the development of major human malignancies, such as breast, colon, lung and prostate cancer. Experimental therapies aimed at inhibiting IGF signaling in human tumors involve various approaches, including neutralizing antibodies and pharmacological inhibitors of IGF-IR kinase activity. Although there are numerous reports describing the antitumor activity of such agents against human cancer cell lines propagated in vitro or in experimental animals, it remains unclear how soon the existing drugs will have a demonstrable effect in patients. In this review, we will discuss the evidence implicating the IGF signaling system in the pathology of human cancer and the various strategies that have so far been developed to target the IGF-IR.


Assuntos
Antineoplásicos/uso terapêutico , Receptor IGF Tipo 1/fisiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Humanos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/fisiopatologia
6.
PLoS One ; 9(4): e94132, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24718026

RESUMO

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancer and plays a crucial role in glioblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K isoforms as a novel anti-tumor approach in glioblastoma. Consistent expression of the PI3K catalytic isoform PI3K p110α was detected in a panel of glioblastoma patient samples. In contrast, PI3K p110ß expression was only rarely detected in glioblastoma patient samples. The expression of a module comprising the epidermal growth factor receptor (EGFR)/PI3K p110α/phosphorylated ribosomal S6 protein (p-S6) was correlated with shorter patient survival. Inhibition of PI3K p110α activity impaired the anchorage-dependent growth of glioblastoma cells and induced tumor regression in vivo. Inhibition of PI3K p110α or PI3K p110ß also led to impaired anchorage-independent growth, a decreased migratory capacity of glioblastoma cells, and reduced the activation of the Akt/mTOR pathway. These effects were selective, because targeting of PI3K p110δ did not result in a comparable impairment of glioblastoma tumorigenic properties. Together, our data reveal that drugs targeting PI3K p110α can reduce growth in a subset of glioblastoma tumors characterized by the expression of EGFR/PI3K p110α/p-S6.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/enzimologia , Adesão Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Classe Ia de Fosfatidilinositol 3-Quinase/fisiologia , Ensaios de Seleção de Medicamentos Antitumorais , Indução Enzimática , Glioblastoma/enzimologia , Humanos , Hidrazonas/farmacologia , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Células Tumorais Cultivadas
7.
Anticancer Res ; 32(8): 3015-27, 2012 08.
Artigo em Inglês | MEDLINE | ID: mdl-22843869

RESUMO

BACKGROUND: Eight human catalytic phosphoinositide 3-kinase (PI3K) isoforms exist which are subdivided into three classes. While class I isoforms have been well-studied in cancer, little is known about the functions of class II PI3Ks. MATERIALS AND METHODS: The expression pattern and functions of the class II PI3KC2ß isoform were investigated in a panel of tumour samples and cell lines. RESULTS: Overexpression of PI3KC2ß was found in subsets of tumours and cell lines from acute myeloid leukemia (AML), glioblastoma multiforme (GBM), medulloblastoma (MB), neuroblastoma (NB), and small cell lung cancer (SCLC). Specific pharmacological inhibitors of PI3KC2ß or RNA interference impaired proliferation of a panel of human cancer cell lines and primary cultures. Inhibition of PI3KC2ß also induced apoptosis and sensitised the cancer cells to chemotherapeutic agents. CONCLUSION: Together, these data show that PI3KC2ß contributes to proliferation and survival in AML, brain tumours and neuroendocrine tumours, and may represent a novel target in these malignancies.


Assuntos
Neoplasias Encefálicas/patologia , Proliferação de Células , Isoenzimas/metabolismo , Leucemia Mieloide Aguda/patologia , Tumores Neuroendócrinos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Taxa de Sobrevida , Animais , Linhagem Celular Tumoral , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Inibidores de Fosfoinositídeo-3 Quinase
8.
Recent Pat DNA Gene Seq ; 1(1): 9-23, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-19075915

RESUMO

Phosphoinositide 3-kinases (PI3Ks) play an essential role in the signal transduction events initiated by the binding of extracellular signals to their cell surface receptors. There are eight known PI3Ks in humans, which have been subdivided into three classes (I-III). The class I(A) of PI3K comprises the p110alpha, p110beta and p110delta isoforms, which associate with receptor tyrosine kinases (RTKs). On the other hand, the class I(B) PI3K p110gamma is regulated by G-protein-coupled receptors (GPCRs). Gene targeting studies in mice have revealed specific biological functions for the class I(A) p110delta in lymphocyte activation, and the class I(B) p110gamma in inflammatory cell responses. In human cancer, recent reports have described activating mutations in the PIK3CA gene encoding p110alpha, and inactivating mutations in the PTEN gene, a tumor suppressor and antagonist of the PI3K pathway. Thus, individual PI3K isoforms are potential drug targets for a variety of human diseases, including allergies, cancer, rheumatoid arthritis and arterial thrombosis. In this review, we will discuss recent patents relating to class I PI3Ks, including patents on the cDNA sequences of p110gamma and p110delta. Moreover, we will review patents on novel pharmacological PI3K inhibitors and on methods of manipulating T cell responses through PI3K.


Assuntos
Descoberta de Drogas/métodos , Patentes como Assunto , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , DNA Complementar , Marcação de Genes , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia
9.
Int J Cancer ; 119(11): 2527-38, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16988940

RESUMO

The potential of the novel insulin-like growth factor receptor (IGF-IR) inhibitor NVP-AEW541 as an antiproliferative agent in human neuroblastoma was investigated. Proliferation of a panel of neuroblastoma cell lines was inhibited by NVP-AEW541 with IC(50) values ranging from 0.15 to 5 microM. Experiments using an IGF-IR neutralizing antibody confirmed that the IGF-IR was essential to support growth of neuroblastoma cell lines. The expression levels of the IGF-IR in individual neuroblastoma cell lines did not correlate with the sensitivities to NVP-AEW541, while coexpression of the IGF-IR and the insulin receptor (IR) correlated with lower sensitivity to the inhibitor in some cell lines. Intriguingly, high levels of activation of Akt/protein kinase B (PKB) and phosphorylation of the ribosomal S6 protein were observed in neuroblastoma cell lines with decreased sensitivities to NVP-AEW541. Inhibition of Akt/PKB activity restored the sensitivity of neuroblastoma cells to the IGF-IR inhibitor. Transfection of neuroblastoma cells with activated Akt or ribosomal protein S6 kinase (S6K) decreased the sensitivity of the cells to NVP-AEW541. IGF-I-stimulated proliferation of neuroblastoma cell lines was completely blocked by NVP-AEW541, or by a combination of an inhibitor of phosphoinositide 3-kinase and rapamycin. In addition to its antiproliferative effects, NVP-AEW541 sensitized neuroblastoma cells to cisplatin-induced apoptosis. Together, our data demonstrate that NVP-AEW541 in combination with Akt/PKB inhibitors or chemotherapeutic agents may represent a novel approach to target human neuroblastoma cell proliferation.


Assuntos
Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Humanos , Neuroblastoma/metabolismo , Transdução de Sinais
10.
Glia ; 53(2): 147-57, 2006 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-16206162

RESUMO

Regulated cell proliferation is a crucial prerequisite for Schwann cells to achieve myelination in development and regeneration. In the present study, we have investigated the function of the cell cycle inhibitors p21 and p16 as potential regulators of Schwann cell proliferation, using p21- or p16-deficient mice. We report that both inhibitors are required for proper withdrawal of Schwann cells from the cell cycle during development and following injury. Postnatal Schwann cells express p21 exclusively in the cytoplasm, first detectable at postnatal day 7. This cytoplasmic p21 expression is necessary for proper Schwann cell proliferation control in the late development of peripheral nerves. After axonal damage, p21 is found in Schwann cell nuclei during the initiation of the proliferation period. This stage is critically regulated by p21, since loss of p21 leads to a strong increase in Schwann cell proliferation. Unexpectedly, p21 levels are upregulated in this phase suggesting that the role of p21 may be more complex than purely inhibitory for the Schwann cell cycle. However, inhibition of Schwann cell proliferation is the overriding crucial function of p21 and p16 in peripheral nerves as revealed by the consequences of loss-of-function in development and after injury. Different mechanisms appear to underlie the inhibitory function, depending on whether p21 is cytoplasmic or nuclear.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Células de Schwann/efeitos dos fármacos , Adenoviridae/genética , Animais , Western Blotting , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Imunofluorescência , Vetores Genéticos , Técnicas Imunoenzimáticas , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Fibras Nervosas/fisiologia , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Nervo Isquiático/lesões , Pele/lesões , Pele/patologia , Transfecção , Cicatrização
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