RESUMO
Key gene mutations are essential for colorectal cancer (CRC) development; however, how the mutated tumor cells impact the surrounding normal cells to promote tumor progression has not been well defined. Here, we report that PIK3CA mutant tumor cells transmit oncogenic signals and result in malignant transformation of intestinal epithelial cells (IECs) via paracrine exosomal arachidonic acid (AA)-induced H3K4 trimethylation. Mechanistically, PIK3CA mutations sustain SGK3-FBW7-mediated stability of the cPLA2 protein, leading to the synthetic increase in AA, which is transported through exosome and accumulated in IECs. Transferred AA directly binds Menin and strengthens the interactions of Menin and MLL1/2 methyltransferase. Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.
Assuntos
Ácido Araquidônico , Transformação Celular Neoplásica , Montagem e Desmontagem da Cromatina , Classe I de Fosfatidilinositol 3-Quinases , Mutação , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Ácido Araquidônico/metabolismo , Animais , Mutação/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Montagem e Desmontagem da Cromatina/genética , Camundongos , Linhagem Celular Tumoral , Colo/patologia , Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Exossomos/metabolismo , Exossomos/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Histonas/metabolismo , Histonas/genéticaRESUMO
The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089⯱â¯0.007⯵M, which was two orders of magnitude lower than that of bestatin (IC50â¯=â¯9.4⯱â¯0.5⯵M). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10⯵M), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100⯵M in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.
Assuntos
Antineoplásicos/química , Antígenos CD13/antagonistas & inibidores , Leucina/análogos & derivados , Inibidores de Proteases/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Antígenos CD13/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Química Click , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucina/farmacologia , Leucina/uso terapêutico , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Simulação de Acoplamento Molecular , Neovascularização Fisiológica/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
Histone deacetylase inhibitors with desirable pharmacokinetic profiles which can be delivered to solid tumor tissues in large amount might be promising to treat solid tumor effectively. Herein, structural modification of a previously reported tetrahydroisoquinoline-based HDAC inhibitor 1 was carried out to improve its plasma stability for more feasible drug delivery. Among three newly synthesized analogs, the in vitro rat plasma stability of compound 2 (t1/2=630min) was over 5-fold improved than its parent 1 (t1/2=103min). In vitro activity evaluation showed that compound 2 and 1 exhibited similar HDACs inhibitory activity, which was validated by western blot analysis and antiproliferative assay. Moreover, compared with 1, compound 2 exhibited comparable, if not higher, in vivo antitumor activity in a human breast carcinoma (MDA-MB-231) xenograft model.
Assuntos
Benzimidazóis/química , Inibidores de Histona Desacetilases/química , Tetra-Hidroisoquinolinas/química , Animais , Benzimidazóis/uso terapêutico , Benzimidazóis/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Ratos , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/uso terapêutico , Transplante Heterólogo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Myocyte enhancer factor 2A (MEF2A) functions in muscle-specific and/or growth factor-related transcription and is involved in cell growth, survival, and apoptosis. To evaluate the role of this transcription factor in cardiac fibroblasts (CFs) in diabetes mellitus, we performed a series of in vitro and in vivo experiments. We used short hairpin RNA (shRNA) to inhibit the expression of MEF2A in CFs in vitro. Inhibition of MEF2A significantly reduced hyperglycemia-induced CF proliferation and migration, myofibroblast differentiation, matrix metalloproteinase (MMP) activities, and collagen production. Furthermore, MEF2A inhibition attenuated HG-induced activation of the mitogen-activated protein kinase (MAPK), Akt, and TGF-ß1/Smad signaling pathways. For in vivo analysis in a mouse model, type-1 diabetes was induced by streptozotocinand MEF2A expression was knocked down by myocardial injection with lentivirus carrying shRNA-MEF2A. Cardiac function was assessed by echocardiography. Total collagen deposition was assessed by Masson's trichrome and Picrosirius red staining. Knockdown of MEF2A ameliorated diabetes-induced cardiac dysfunction and collagen deposition. Our study suggests that inhibition of MEF2A could alleviate HG-induced extracellular matrix accumulation by blocking the activation of Akt and TGF-ß1/Smad signaling pathway in CFs. Thus, inhibition of MEF2A has therapeutic potential in the treatment of diabetic-induced cardiac remodeling.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Matriz Extracelular/metabolismo , Hiperglicemia/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/patologia , Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Glucose/fisiologia , Ventrículos do Coração/patologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Miocárdio/química , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
A series of new 1,3,4-oxadiazole and 1,2,4-triazole derivatives were synthesized. The structures were confirmed by IR, (1)H-NMR, and MS. The compounds were evaluated for their antiproliferative activity against K562 (human erythromyeloblastoid leukemia cell line), MDA-MB-231 (human breast adenocarcinoma cell line), HT29 (human colon adenocarcinoma grade II cell line) and HepG2 (human hepatocellular liver carcinoma cell line) in vitro. The result showed that 7 compounds displayed inhibitory activities against K562 with the inhibition rate more than 50%. Especially, compound 5f exhibited the most potent activity against K562 with 85% inhibition ratio and could be used as lead compound to search new 1,3,4-oxadiazole derivatives as antiproliferative agent.