RESUMO
Honokiol, a constituent of Magnolia officinalis, has been reported to possess potent anti-cancer activity through targeting multiple signaling pathways in numerous malignancies including acute myeloid leukemia (AML). However, the underlying mechanisms remain to be defined. Here, we report that honokiol effectively decreased enzyme activity of histone deacetylases (HDACs) and reduced the protein expression of class I HDACs in leukemic cells. Moreover, treatment with proteasome inhibitor MG132 prevented honokiol-induced degradation of class I HDACs. Importantly, honokiol increased the levels of p21/waf1 and Bax via triggering acetylation of histone in the regions of p21/waf1 and Bax promoter. Honokiol induced apoptosis, decreased activity of HDACs, and significantly inhibited the clonogenic activity of hematopoietic progenitors in bone marrow mononuclear cells from patients with AML. However, honokiol did not decrease the activity of HDACs and induce apoptosis in normal hematopoietic progenitors from unbilicial cord blood. Finally, honokiol dramatically reduced tumorigenicity in a xenograft leukemia model. Collectively, our findings demonstrate that honokiol has anti-leukemia activity through inhibiting HDACs. Thus, being a relative non-toxic agent, honokiol may serve as a novel natural agent for cancer prevention and therapy in leukemia.
Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Histona Desacetilases/metabolismo , Leucemia Mieloide/tratamento farmacológico , Lignanas/farmacologia , Doença Aguda , Adulto , Idoso , Animais , Biocatálise/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Humanos , Células K562 , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Complexo de Endopeptidases do Proteassoma/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
Peroxiredoxins (Prxs) are potential therapeutic targets for major diseases such as cancers. However, isotype-specific inhibitors remain to be developed. We report that adenanthin, a diterpenoid isolated from the leaves of Rabdosia adenantha, induces differentiation of acute promyelocytic leukemia (APL) cells. We show that adenanthin directly targets the conserved resolving cysteines of Prx I and Prx II and inhibits their peroxidase activities. Consequently, cellular H(2)O(2) is elevated, leading to the activation of extracellular signal-regulated kinases and increased transcription of CCAAT/enhancer-binding protein ß, which contributes to adenanthin-induced differentiation. Adenanthin induces APL-like cell differentiation, represses tumor growth in vivo and prolongs the survival of mouse APL models that are sensitive and resistant to retinoic acid. Thus, adenanthin can serve as what is to our knowledge the first lead natural compound for the development of Prx I- and Prx II-targeted therapeutic agents, which may represent a promising approach to inducing differentiation of APL cells.
Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diterpenos do Tipo Caurano/farmacologia , Diterpenos/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Peroxirredoxinas/antagonistas & inibidores , Animais , Antineoplásicos/química , Proteína beta Intensificadora de Ligação a CCAAT/biossíntese , Cisteína/química , Diterpenos/química , Diterpenos do Tipo Caurano/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Peróxido de Hidrogênio/análise , Camundongos , Peroxirredoxinas/química , Tretinoína/farmacologia , Células Tumorais CultivadasRESUMO
Ikaros is an important transcription factor involved in the development and differentiation of hematopoietic cells. In this work, we found that chemotherapeutic drugs or ultraviolet radiation (UV) treatment could reduce the expression of full-length Ikaros (IK1) protein in less than 3h in leukemic NB4, Kasumi-1 and Jurkat cells, prior to the activation of caspase-3. Etoposide treatment could not alter the mRNA level of IK1 but it could shorten the half-life of IK1. Co-treatment with the proteasome inhibitor MG132 or epoxomicin but not calpain inhibitor calpeptin inhibited etoposide-induced Ikaros downregulation. Overexpression of IK1 could accelerate etoposide-induced apoptosis in NB4 cells, as evidenced by the increase of Annexin V positive cells and the more early activation of caspase 3. To our knowledge, this is the first report to show that upon chemotherapy drugs or UV treatment, IK1 could be degraded via the proteasome system in the early phase of apoptosis induction. These data might shed new insight on the role of IK1 in apoptosis and the post-translational regulation of IK1.
Assuntos
Apoptose , Fator de Transcrição Ikaros/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Etoposídeo/farmacologia , Humanos , Células Jurkat , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos da radiação , Ubiquitina/metabolismo , Raios UltravioletaRESUMO
The transcription factor Ikaros was originally found to function as a key regulator of lymphocyte differentiation. In this study, we provide the first evidence that Ikaros is expressed at higher levels in ovarian cancer tissues compared with normal ovarian tissues and is significantly associated with high FIGO stage and low differentiation state in ovarian serous adenocarcinoma. To this end, we transfected IK1 (full length of Ikaros) into the SKOV3 ovarian cancer cell line and examined cell biological behaviors including proliferation, migration and invasion. We found that overexpression of IK1 inhibited cell proliferation by inducing G1 arrest, accompanied by the upregulation of P27 and P21 and downregulation of cyclin D1 and D2. On the other hand, IK1 increased the migration and invasion of ovarian cancer cells, as assessed by scratch-wound assay, transwell migration assay, and invasion assay. Overexpression of IK1 significantly increased Slug but not Snail1 expression at both mRNA and protein levels. It also downregulated and upregulated E-cadherin and MMP-2, two target genes of Slug involved in migration, respectively. Furthermore, knocking down Slug abrogated IK1-mediated increase in migration and invasion. These data suggest that Slug plays an important role in IK1-induced migration and invasion. In conclusion, we show for the first time that IK1 plays a dual role in the proliferation, migration and invasion of ovarian cancer cells, providing new insights into their metastasis.