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1.
Biochem Biophys Res Commun ; 590: 55-62, 2022 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-34971958

RESUMEN

Cellular senescence is a state of irreversible cell growth arrest that functions as a biological defense mechanism against severe DNA damage. Senescent cells with DNA damage produce pro-inflammatory cytokines, such as IL-6 and IL-8, and this phenomenon is called the senescence-associated secretory phenotype (SASP). SASP factors have been implicated in various disorders, including cancer. We performed a screening assay and identified oridonin as a candidate SASP inhibitor. Oridonin is an active diterpenoid that is isolated from Isodon plants and has been reported to exhibit anti-inflammatory, antibacterial, antioxidant, and antitumor activities. It reduced the secretion of IL-6 and IL-8 in senescent cells at the protein and mRNA levels. Oridonin also inhibited p65 subunit of NF-κB activity. However, oridonin did not affect SA ß-gal activity and enhanced the expression of p21. The expression and phosphorylation of p38 were down-regulated by oridonin. The p38 inhibitor SB203580 inhibited the secretion of IL-8, slightly inhibited the secretion of IL-6, and did not affect NF-κB activity. Therefore, the NF-κB and p38 pathways may contribute to the inhibition of SASP by oridonin. Oridonin has potential as a therapeutic agent for SASP-related diseases.


Asunto(s)
Senescencia Celular , Diterpenos de Tipo Kaurano/farmacología , FN-kappa B/metabolismo , Fenotipo Secretor Asociado a la Senescencia , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Bleomicina , Línea Celular , Senescencia Celular/efectos de los fármacos , Humanos , Fenotipo Secretor Asociado a la Senescencia/efectos de los fármacos
2.
Commun Biol ; 5(1): 564, 2022 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-35681048

RESUMEN

Cyclins and cyclin-dependent kinases (CDKs) regulate the cell cycle, which is important for cell proliferation and development. Cyclins bind to and activate CDKs, which then drive the cell cycle. The expression of cyclins periodically changes throughout the cell cycle, while that of CDKs remains constant. To elucidate the mechanisms underlying the constant expression of CDKs, we search for compounds that alter their expression and discover that the natural product fucoxanthinol downregulates CDK2, 4, and 6 expression. We then develop a method to immobilize a compound with a hydroxyl group onto FG beads® and identify human ribosomal protein uS7 (also known as ribosomal protein S5) as the major fucoxanthinol-binding protein using the beads and mass spectrometry. The knockdown of uS7 induces G1 cell cycle arrest with the downregulation of CDK6 in colon cancer cells. CDK6, but not CDK2 or CDK4, is degraded by the depletion of uS7, and we furthermore find that uS7 directly binds to CDK6. Fucoxanthinol decreases uS7 at the protein level in colon cancer cells. By identifying the binding proteins of a natural product, the present study reveals that ribosomal protein uS7 may contribute to the constant expression of CDK6 via a direct interaction.


Asunto(s)
Productos Biológicos , Neoplasias del Colon , Quinasa 6 Dependiente de la Ciclina , Proteínas Ribosómicas , beta Caroteno , Productos Biológicos/farmacología , Quinasa 2 Dependiente de la Ciclina , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina/genética , Ciclinas/metabolismo , Humanos , Proteínas Ribosómicas/genética , beta Caroteno/análogos & derivados , beta Caroteno/farmacología
3.
Int J Oncol ; 56(3): 848-856, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32124968

RESUMEN

Squamous cell lung carcinoma (SQCLC) is an aggressive type of lung cancer. In contrast with the marked advances that have been achieved in the treatment of lung adenocarcinoma, there are currently no effective targeted therapies for SQCLC, for with cytotoxic drugs are still the main treatment strategy. Therefore, the present study aimed to develop novel combination therapies for SQCLC. The results demonstrated that a combined treatment with the potent histone deacetylase (HDAC) inhibitor OBP­801 and the third­generation anthracycline amrubicin synergistically inhibited the viability of SQCLC cell lines by inducing apoptosis signal­regulating kinase 1 (ASK1)­dependent, as well as JNK­ and p38 mitogen­activated protein kinase (MAPK)­independent apoptosis. OBP­801 treatment strongly induced the protein expression levels of thioredoxin­interacting protein (TXNIP), and amrubicin treatment increased the levels of intracellular reactive oxygen species (ROS), which suggested that this combination oxidized and dissociated thioredoxin 2 (Trx2) from mitochondrial ASK1 and activated ASK1. Moreover, mouse xenograft experiments using human H520 SQCLC cells revealed that the co­treatment potently suppressed tumor growth in vivo. These results suggested that a combined treatment with OBP­801 and amrubicin may have potential as a therapeutic strategy for SQCLC.


Asunto(s)
Antraciclinas/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , MAP Quinasa Quinasa Quinasa 5/metabolismo , Péptidos Cíclicos/administración & dosificación , Animales , Antraciclinas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Péptidos Cíclicos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Oncol Rep ; 38(5): 3205-3210, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29048653

RESUMEN

The X-linked inhibitor of apoptosis (XIAP) confers the resistance of various types of cancer to standard chemotherapeutic agents such as anthracycline and taxane. In breast cancer, XIAP is known to be overexpressed. However, the mechanisms underlying the overexpression of XIAP remain currently unclear. In order to elucidate the mechanisms responsible for the overexpression of the XIAP protein in breast cancer, we attempted to clarify the mechanisms by which the natural compound curcumin downregulates XIAP in breast cancer cells. In that process, we identified the ribosomal protein S3 (RPS3) as a curcumin­binding protein using curcumin-fixed magnetic FG beads. The knockdown of RPS3 inhibited cell growth and induced apoptosis as well as the downregulation of XIAP in breast cancer cells. Although RPS3 is known to directly bind to and activate the nuclear factor-κB (NF-κB), which induces several anti-apoptotic genes such as XIAP, the knockdown of RPS3 unexpectedly reduced the levels of the XIAP protein, but not the mRNA level of XIAP and the transcription factor NF-κB activity. These results reveal that RPS3 upregulates XIAP independently of the NF-κB pathway in human breast cancer cells.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Proteínas Ribosómicas/genética , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias de la Mama/patología , Proteínas Portadoras/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Curcumina/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , FN-kappa B/genética , Proteínas Ribosómicas/antagonistas & inhibidores
5.
PLoS One ; 8(2): e55922, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23431365

RESUMEN

Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human Apo2L/TRAIL has been under clinical trials, whereas various kinds of malignant tumors have resistance to Apo2L/TRAIL. We and others have shown that several anticancer agents and flavonoids overcome resistance to Apo2L/TRAIL by upregulating death receptor 5 (DR5) in malignant tumor cells. However, the mechanisms by which these compounds induce DR5 expression remain unknown. Here we show that the dietary flavonoid apigenin binds and inhibits adenine nucleotide translocase-2 (ANT2), resulting in enhancement of Apo2L/TRAIL-induced apoptosis by upregulation of DR5. Apigenin and genistein, which are major flavonoids, enhanced Apo2L/TRAIL-induced apoptosis in cancer cells. Apigenin induced DR5 expression, but genistein did not. Using our method identifying the direct targets of flavonoids, we compared the binding proteins of apigenin with those of genistein. We discovered that ANT2 was a target of apigenin, but not genistein. Similarly to apigenin, knockdown of ANT2 enhanced Apo2L/TRAIL-induced apoptosis by upregulating DR5 expression at the post-transcriptional level. Moreover, silencing of ANT2 attenuated the enhancement of Apo2L/TRAIL-induced apoptosis by apigenin. These results suggest that apigenin upregulates DR5 and enhances Apo2L/TRAIL-induced apoptosis by binding and inhibiting ANT2. We propose that ANT2 inhibitors may contribute to Apo2L/TRAIL therapy.


Asunto(s)
Translocador 2 del Nucleótido Adenina/metabolismo , Antineoplásicos/farmacología , Apigenina/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Translocador 2 del Nucleótido Adenina/antagonistas & inhibidores , Translocador 2 del Nucleótido Adenina/genética , Apigenina/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Sinergismo Farmacológico , Técnicas de Silenciamiento del Gen , Genisteína/química , Humanos , Masculino , Unión Proteica , ARN Interferente Pequeño/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Regulación hacia Arriba/efectos de los fármacos
6.
PLoS One ; 8(8): e73219, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24009741

RESUMEN

Flavonoids have been reported to inhibit tumor growth by causing cell cycle arrest. However, little is known about the direct targets of flavonoids in tumor growth inhibition. In the present study, we developed a novel method using magnetic FG beads to purify flavonoid-binding proteins, and identified ribosomal protein S9 (RPS9) as a binding partner of the flavonoid apigenin. Similar to treatment with apigenin, knockdown of RPS9 inhibited the growth of human colon cancer cells at the G2/M phase by downregulating cyclin-dependent kinase 1 (CDK1) expression at the promoter level. Furthermore, knockdown of RPS9 suppressed G2/M arrest caused by apigenin. These results suggest that apigenin induces G2/M arrest at least partially by directly binding and inhibiting RPS9 which enhances CDK1 expression. We therefore raise the possibility that identification of the direct targets of flavonoids may contribute to the discovery of novel molecular mechanisms governing tumor growth.


Asunto(s)
Apigenina/farmacología , Proteína Quinasa CDC2/genética , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Ribosómicas/metabolismo , Apigenina/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Técnicas de Silenciamiento del Gen , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase M del Ciclo Celular/genética , Regiones Promotoras Genéticas , Unión Proteica , Proteína Ribosómica S9 , Proteínas Ribosómicas/genética
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