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1.
J Endocrinol Invest ; 46(12): 2609-2616, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37233978

RESUMO

PURPOSE: Clinical control of corticotroph tumors is difficult to achieve since they usually persist or relapse after surgery. Pasireotide is approved to treat patients with Cushing's disease for whom surgical therapy is not an option. However, Pasireotide seems to be effective only in a sub-set of patients, highlighting the importance to find a response marker to this approach. Recent studies demonstrated that the delta isoform of protein kinase C (PRKCD) controls viability and cell cycle progression of an in vitro model of ACTH-secreting pituitary tumor, the AtT-20/D16v-F2 cells. This study aims at exploring the possible PRKCD role in mediating Pasireotide effects. METHODS: It was assessed cell viability, POMC expression and ACTH secretion in AtT20/D16v-F2 cells over- or under-expressing PRKCD. RESULTS: We found that Pasireotide significantly reduces AtT20/D16v-F2 cell viability, POMC expression and ACTH secretion. In addition, Pasireotide reduces miR-26a expression. PRKCD silencing decreases AtT20/D16v-F2 cell sensitivity to Pasireotide treatment; on the contrary, PRKCD overexpression increases the inhibitory effects of Pasireotide on cell viability and ACTH secretion. CONCLUSION: Our results provide new insights into potential PRKCD contribution in Pasireotide mechanism of action and suggest that PRKCD might be a possible marker of therapeutic response in ACTH-secreting pituitary tumors.


Assuntos
Hipersecreção Hipofisária de ACTH , Neoplasias Hipofisárias , Humanos , Neoplasias Hipofisárias/patologia , Corticotrofos/metabolismo , Corticotrofos/patologia , Proteína Quinase C-delta/metabolismo , Proteína Quinase C-delta/farmacologia , Proteína Quinase C-delta/uso terapêutico , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/farmacologia , Hormônio Adrenocorticotrópico/metabolismo , Recidiva Local de Neoplasia/patologia , Linhagem Celular , Hipersecreção Hipofisária de ACTH/metabolismo , Linhagem Celular Tumoral
2.
Cell Death Dis ; 9(2): 23, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29348560

RESUMO

Protein kinase C (PKC) isozymes play major roles in human diseases, including cancer. Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, we report the first small-molecule PKCδ-selective activator, the 7α-acetoxy-6ß-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKCδ-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKCδ-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKCδ but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKCδ-dependent manner. Additionally, the impairment of colonosphere growth and formation, associated with depletion of stemness markers, indicate that Roy-Bz also targets drug-resistant cancer stem cells, preventing tumor dissemination and recurrence. Notably, in xenograft mouse models, Roy-Bz showed a PKCδ-dependent antitumor effect, through anti-proliferative, pro-apoptotic, and anti-angiogenic activities. Besides, Roy-Bz was non-genotoxic, and in vivo it had no apparent toxic side effects. Collectively, our findings reveal a novel promising anticancer drug candidate. Most importantly, Roy-Bz opens the way to a new era on PKC biology and pharmacology, contributing to the potential redefinition of the structural requirements of isozyme-selective agents, and to the re-establishment of PKC isozymes as feasible therapeutic targets in human diseases.


Assuntos
Neoplasias do Colo/terapia , Proteína Quinase C-delta/uso terapêutico , Neoplasias do Colo/patologia , Humanos , Proteína Quinase C-delta/farmacologia
3.
Mol Biol Cell ; 22(8): 1398-408, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21346188

RESUMO

Vaccinia-related kinase 1 (VRK1) is a novel serine/threonine kinase that plays an important role in cell proliferation. However, little is known about the upstream regulators of VRK1 activity. Here we provide evidence for a role of protein kinase Cδ (PKCδ) in the regulation of murine VRK1. We show that PKCδ interacts with VRK1, phosphorylates the Ser-355 residue in the putative regulatory region, and negatively regulates its kinase activity in vitro. Intriguingly, PKCδ-induced cell death was facilitated by phosphorylation of VRK1 when cells were exposed to a DNA-damaging agent. In addition, p53 played a critical role in the regulation of DNA damage-induced cell death accompanied by PKCδ-mediated modulation of VRK1. In p53-deficient cells, PKCδ-mediated phosphorylation of VRK1 had no effect on cell viability. However, cells overexpressing p53 exhibited significant reduction of cell viability when cotransfected with both VRK1 and PKCδ. Taken together, these results indicate that PKCδ regulates phosphorylation and down-regulation of VRK1, thereby contributing to cell cycle arrest and apoptotic cell death in a p53-dependent manner.


Assuntos
Proteína Quinase C-delta/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas Recombinantes de Fusão/metabolismo , Serina/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Transformada , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clonagem Molecular , Cricetinae , Dano ao DNA/efeitos dos fármacos , Eletroporação , Escherichia coli , Etoposídeo/farmacologia , Feminino , Regulação da Expressão Gênica , Inativação Gênica , Humanos , Camundongos , Mutação , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Proteína Quinase C-delta/genética , Proteína Quinase C-delta/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteína Supressora de Tumor p53/genética
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