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The current work demonstrates the synthesis and characterization of piperic acid conjugates with homochiral/heterochiral dipeptides containing phenylalanine as anti-skin cancer agents. The conjugates PA-DPhe-LPhe-OH, FC-1; PA-LPhe-DPhe-OH, FC-2; PA-DPhe-DPhe-OH, FC-3; and PA-DPhe-DPhe-OH, FC-4 were synthesized, characterized and assessed for cytotoxicity against melanoma cell lines of human and murine origin. Among all, PA-DPhe-DPhe-OH (FC-3) conjugate was identified as a potential cytotoxic lead against melanoma cells by delineating the anti-proliferative and anti-migratory potential together with its anti-inflammatory potential against pro-inflammatory interleukins (IL-1ß, IL-6, and IL-8). Evidences from western blotting, fractionation, and immunocytochemistry experiments suggest that Stat-3 is a critical signaling molecule involved in the FC-3 mechanism of action. The results denote that FC-3 profoundly ablates Stat-3 expression, phosphorylation, and nuclear translocation. Stat-3 mRNA analysis revealed that FC-3 did not alter the transcription of Stat-3. However, in cells where proteasome mediated degradation was inhibited, FC-3 failed to check the Stat-3 expression implying that FC-3 augments the proteasomal degradation of Stat-3. Of note, FC-3 failed to reverse the IL-6 mediated hyperactivation of Stat-3 in A375 cells. Critically, in Stat-3 deficient cancer cells, the anti-clonogenic and anti-migratory potential of FC-3 was significantly subdued. Further, the in vivo efficacy of FC-3 was validated in the two-step (DMBA/TPA) chemically induced mouse skin cancer model. The FC-3-treated cohorts of mice unveiled a significant decrease in the cumulative number of tumors besides attenuation of tumor growth with respect to the vehicle-treated mice. Lastly, in corroboration with our in vitro findings, serum collected from mice groups at various intervals during the treatment regimen demonstrated decrement in IL-1ß and IL-6 levels in FC-3 treated groups compared to the vehicle-treated group.
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Antineoplásicos , Melanoma , Neoplasias Cutáneas , Ratones , Humanos , Animales , Interleucina-6/genética , Fenilalanina/química , Dipéptidos/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Antineoplásicos/farmacología , Interleucina-1betaRESUMEN
ATF-4 is a master regulator of transcription of genes essential for cellular-adaptive function. In response to the quantum and duration of stress, ATF-4 diligently responds to both pro-apoptotic and pro-survival signals converging into either autophagy or apoptosis/senescence. Despite emerging cues implying a relationship between autophagy and senescence, how these two processes are controlled remains unknown. Herein, we demonstrate ß-(4-fluorobenzyl) Arteannuin B (here after Arteannuin 09), a novel semisynthetic derivative of Arteannuin B, as a potent ER stress inducer leading to the consistent activation of ATF-4. Persistent ATF-4 expression at early time-points facilitates the autophagy program and consequently by upregulating p21 at later time-points, the signaling is shifted towards G2/M cell cycle arrest. As bZIP transcription factors including ATF-4 are obligate dimers, and because ATF-4 homodimers are not highly stable, we hypothesized that ATF-4 may induce p21 expression by physically interacting with another bZIP family member i.e., C/EBPß. Our co-immunoprecipitation and co-localization studies demonstrated that ATF-4 is principally responsible for the autophagic potential of Arteannuin 09, while as, induction of both ATF-4 and C/EBPß is indispensable for the p21 regulated-cell cycle arrest. Interestingly, inhibition of autophagy signaling switches the fate of Arteannuin 09 treated cells from senescence to apoptosis. Lastly, our data accomplished that Arteannuin 09 is a potent inhibitor of tumor growth and inducer of premature senescence in vivo.
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In recent years, significant progress has been made to the use-case of small peptides because of their diversified edifice and hence their versatile application scope in cancer therapy. Here we identify the heterochiral dipeptide H-D Phe-L Phe-OH (F1) as a potent inducer of the metastatic suppressor NM23H1. We divulge the effect of F1 on the major EMT/metastasis-associated genes and the implications on the invasion and migration ability of cancer cells. The anti-invasive potential of F1 was directly correlated with NM23H1 expression. Mechanistically, F1 treatment elevated p53 levels as validated by localization and transcriptional studies. In the NM23H1 knockdown condition, F1 failed to induce any p53 expression/nuclear localization, indicating that the upregulation in p53 expression by F1 is NM23H1 dependent. We also demonstrate how the antimetastatic potential of F1 is primarily mediated through NM23H1 irrespective of the p53 status of the cell. However, both NM23H1 and a functional p53 protein in conjunction govern the apoptotic and cytostatic potential of F1. Coimmunoprecipitation studies unraveled the augmentation of the p53 and NM23H1 interaction in p53 wild-type cells. However, in p53 mutated cells, no such enrichment was evidenced. We employed mouse isogenic cell lines (4T-1 and 4T-1 p53) to determine the in vivo efficacy of F1 (spontaneous and experimental models). Decreased tumor volume in the cohort injected with 4T-1 p53 cells demonstrated that while the antimetastatic potential of F1 was reliant on NM23H1, p53 activation was required for ablation of primary tumor burden. Our findings unravel that F1 treatment induces significant abrogation of the migration, invasion and metastatic potential of both p53 wild-type and p53 deficient cancers mediated through NM23H1.
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Neoplasias , Proteína p53 Supresora de Tumor , Ratones , Animales , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Dipéptidos/farmacología , Dipéptidos/metabolismo , Fenilalanina/farmacología , Línea Celular , Línea Celular TumoralRESUMEN
Epithelial-mesenchymal transition (EMT) is critical for the metastatic dissemination of cancer cells and contributes to drug resistance. In this study, we observed that epithelial colorectal cancer (CRC) cells transiently exposed to 5-fluorouracil (5-FU) (a chemotherapeutic drug for CRC) as well as 5-FU-resistant cells (5-FU-R) develop EMT characters as evidenced by activation of Vimentin and augmented invasive properties. On the other hand, 4DPG (4'-demethyl-deoxypodophyllotoxin glucoside), a natural podophyllotoxin analog attenuates EMT and invadopodia formation abilities of HCT-116/5-FU-R and SW-620/5-FU-R cells. Treatment with 4DPG restrains Vimentin phosphorylation (Ser38) in 5-FU-R cells, along with downregulation of mesenchymal markers Twist1 and MMP-2 while augmenting the expression of epithelial markers E-cadherin and TIMP-1. Moreover, 4DPG boosts the tumor-suppressor protein, checkpoint kinase 2 (Chk2) via phosphorylation at Thr68 in a dose-dependent manner in 5-FU-R cells. Mechanistically, SiRNA-mediated silencing of Chk2, as well as treatment with Chk2-specific small-molecule inhibitor (PV1019), divulges that 4DPG represses Vimentin activation in a Chk2-dependent manner. Furthermore, immunoprecipitation analysis unveiled that 4DPG prevents complex formation between Vimentin and p53 resulting in the rescue of p53 and its nuclear localization in aggressive 5-FU-R cells. In addition, 4DPG confers suitable pharmacokinetic properties and strongly abrogates tumor growth, polyps formation, and lung metastasis in an orthotopic rat colorectal carcinoma model. In conclusion, our findings demonstrate 4DPG as a targeted antitumor/anti-metastatic pharmacological lead compound to circumvent EMT-associated drug resistance and suggest its clinical benefits for the treatment of aggressive cancers.
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The last decade has witnessed a substantial expansion in the field of microRNA (miRNA) biology, providing crucial insights into the role of miRNAs in disease pathology, predominantly in cancer progression and its metastatic spread. The discovery of tumor-suppressing miRNAs represents a potential approach for developing novel therapeutics. In this context, through miRNA microarray analysis, we examined the consequences of Prostate apoptosis response-4 (Par-4), a well-established tumor-suppressor, stimulation on expression of different miRNAs in Panc-1 cells. The results strikingly indicated elevated miR-200c levels in these cells upon Par-4 overexpression. Intriguingly, the Reverse Phase Protein Array (RPPA) analysis revealed differentially expressed proteins (DEPs), which overlap between miR200c- and Par-4-transfected cells, highlighting the cross-talks between these pathways. Notably, Phospho-p44/42 MAPK; Bim; Bcl-xL; Rb Phospho-Ser807, Ser811; Akt Phospho-Ser473; Smad1/5 Phospho-Ser463/Ser465 and Zyxin scored the most significant DEPs among the two data sets. Furthermore, the GFP-Par-4-transfected cells depicted an impeded expression of critical mesenchymal markers viz. TGF-ß1, TGF-ß2, ZEB-1, and Twist-1, concomitant with augmented miR-200c and E-cadherin levels. Strikingly, while Par-4 overexpression halted ZEB-1 at the transcriptional level; contrarily, silencing of endogenous Par-4 by siRNA robustly augmented the Epithelial-mesenchymal transition (EMT) markers, along with declining miR-200c levels. The pharmacological Par-4-inducer, NGD16, triggered Par-4 expression which corresponded with increased miR-200c resulting in the ZEB-1 downregulation. Noteworthily, tumor samples obtained from the syngenic mouse pancreatic cancer model revealed elevated miR-200c levels in the NGD16-treated mice that positively correlated with the Par-4 and E-cadherin levels in vivo; while a negative correlation was evident with ZEB-1 and Vimentin.
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BACKGROUND: We recently reported prostate apoptosis response 4 (Par-4), a potential tumor suppressor protein restrains epithelial-mesenchymal transition (EMT) properties and promotes mesenchymal-epithelial transition (MET) in invasive cancer cells by repressing Twist-1 promoter activity. Here, we demonstrate that genetic as well as pharmacological modulation of Par-4 by NGD16 (a small molecule antimetastatic agent), limits EMT-induced chemoresistance in aggressive cancer cells by suppressing MDM-2, a downstream effector of Twist-1. METHODS: Matrigel invasion assay, gelatin degradation assay, cell scattering assay, MTT assay and colony formation assay were used to study the proliferation and migration abilities of invasive cancer cells. Immunoblotting, immunocytochemistry, and immunoprecipitation analysis were utilized for determining protein expression and protein-protein interaction. 4T1 aggressive mouse carcinoma model was employed to evaluate tumor growth and lung metastasis. RESULTS: Treatment of gemcitabine (nucleoside analogue anticancer agent) to pancreatic cancer (Panc-1, MiaPaca-2) and breast cancer (MDA-MB-231) cells amplified MDM-2 expression along with increase in EMT properties. Conversely, NGD16 boosted expression of tumor suppressor Par-4 and inhibited invasion and migration abilities of these cells. Moreover, induction of Par-4 effectively diminished MDM-2 along with pro-EMT markers, whereas, augmented the expression of epithelial markers. Furthermore, siRNA-mediated silencing of Par-4 divulged that NGD16 exerts its EMT inhibitory effects in a Par-4-dependent manner. Mechanistically, Par-4 activation provokes p53 by disrupting MDM-2-p53 interaction, which restored epithelial characteristics in cancer cells. Additionally, partial knockdown of MDM-2 through siRNA pronounced the anti-proliferative and anti-invasive effects of NGD16. Finally, NGD16 efficiently inhibited tumor growth and lung metastasis in mouse mammary carcinoma model without showing any undesirable effects. CONCLUSION: Our findings unveil Par-4 as a key therapeutic target and NGD16 (the pharmacological modulator of Par-4) are potential tools to suppress EMT and associated chemoresistance, which could be exploited clinically for the treatment of aggressive cancers.
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Neoplasias de la Mama , Neoplasias Pancreáticas , Animales , Antineoplásicos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Movimiento Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Ratones , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Receptores de Trombina , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias PancreáticasRESUMEN
Drug induced resistance is a widespread problem in the clinical management of cancer. Cancer cells, when exposed to cytotoxic drugs, can reprogram their cellular machinery and resist cell death. Evasion of cell death mechanisms, such as apoptosis and necroptosis, are part of a transcriptional reprogramming that cancer cells utilize to mediate cytotoxic threats. An additional strategy adopted by cancer cells to resist cell death is to initiate the epithelial to mesenchymal transition (EMT) program. EMT is a trans-differentiation process which facilitates a motile phenotype in cancer cells which can be induced when cells are challenged by specific classes of cytotoxic drugs. Induction of EMT in malignant cells also results in drug resistance. In this setting, therapy-induced senescence (TIS), an enduring "proliferative arrest", serves as an alternate approach against cancer because cancer cells remain susceptible to induced senescence. The molecular processes of senescence have proved challenging to understand. Senescence has previously been described solely as a tumor-suppressive mechanism; however, recent evidences suggest that senescence-associated secretory phenotype (SASP) can contribute to tumor progression. SASP has also been identified to contribute to EMT induction. Even though the causes of senescence and EMT induction can be wholly different from each other, a functional link between EMT and senescence is still obscure. In this review, we summarize the evidence of potential cross-talk between EMT and senescence while highlighting some of the most commonly identified molecular players. This review will shed light on these two intertwined and highly conserved cellular process, while providing background of the therapeutic implications of these processes.
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Epithelial to mesenchymal transitions (EMT) is a preparatory process for cancer cells to attain motility and further metastasis to distant sites. Majority of DNA damaging drugs have shown to develop EMT as one of the major mechanisms to attain drug resistance. Here we sought to understand the resistance/survival instincts of cancer cells during initial phase of drug treatment. We provide a tangible evidence of stimulation of EMT factors in Apc knockout colorectal carcinoma model. Our results implied that CPT-treated Apc knockout cohorts depicted increased pro-invasive and pro-survival factors (Vimentin/pser38Vimentin & NFκB). Moreover, by cell sorting experiment, we have observed the expression of Vimentin in early apoptotic cells (AnnexinV positive) from 36 to 48 h of CPT treatment. We also observed the expression of chimeric Sec-AnnexinV-mvenus protein in migrated cells on transwell membrane recapitulating signatures of early apoptosis. Notably, induction of Vimentin-mediated signaling (by CPT) delayed apoptosis progression in cells conferring survival responses by modulating the promoter activity of NFκB. Furthermore, our results unveiled a novel link between Vimentin and ATM signaling, orchestrated via binding interaction between Vimentin and ATM kinase. Finally, we observed a significant alteration of crypt-villus morphology upon combination of DIM (EMT inhibitor) with CPT nullified the background EMT signals thus improving the efficacy of the DNA damaging agent. Thus, our findings revealed a resistance strategy of cancer cells within a very initial period of drug treatment by activating EMT program, which hinders the cancer cells to achieve later phases of apoptosis thus increasing the chances of early migration.
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Apoptosis , Neoplasias Colorrectales/metabolismo , Daño del ADN , Transición Epitelial-Mesenquimal , Vimentina/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Camptotecina/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Vimentina/genéticaRESUMEN
PURPOSE: More than 90% of the breast cancer deaths occur due to the metastasis of the cancer cells to secondary organ sites. Increased Glucose-regulated protein 78 (GRP78) expression is critical for epithelial-mesenchymal transition (EMT) and invasion in breast cancer resulting in poor patient survival outcomes. Therefore, there is an urgent need of potential inhibitors of GRP78 for the abrogation of invasion and metastasis in breast cancer. METHODS: We investigated the effect of IKM5 (2-(1-(1H-indol-3-yl)octyl)-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one) (a novel Indolylkojyl methane analogue) on invasion abilities of human breast cancer cells employing invadopodia formation, Matrigel invasion assays, and mouse models for metastasis. The mechanism underlying the anti-invasive effect of IKM5 was examined through molecular docking, immunoblotting, immunocytochemistry, co-immunoprecipitation analysis, siRNA silencing, and sub-cellular fractionation studies. RESULTS: Treatment with IKM5 at its sub-toxic concentration (200 nM) suppressed invasion and invadopodia formation, and growth factor-induced cell scattering of aggressive human breast cancer MDA-MB-231, MDA-MB-468, and MCF7 cells. IKM5 spontaneously binds to GRP78 (Ki = 1.35 µM) and downregulates its expression along with the EMT markers MMP-2, Twist1, and Vimentin. Furthermore, IKM5 amplified the expression and nuclear translocation of tumor suppressor Par-4 to control NF-kB-mediated pro-EMT activities. Interestingly, IKM5 disrupts the interaction between GRP78 and TIMP-1 by inhibiting GRP78 in a Par-4-dependent manner. Moreover, IKM5 inhibited tumor growth and lung metastasis at a safe dose of 30 mg/kg/body weight. CONCLUSION: Our study warrants IKM5, a potential anticancer agent that can abrogate invasion and metastasis, suggesting its clinical development for the treatment of patients with advanced breast cancer.
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Antineoplásicos/farmacología , Proteínas de Choque Térmico/genética , Metano/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Doxorrubicina/farmacología , Chaperón BiP del Retículo Endoplásmico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Humanos , Metaloproteinasas de la Matriz , Metano/análogos & derivados , Metano/química , Metano/farmacocinética , Ratones , Modelos Biológicos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Transporte de Proteínas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Organic nanoparticles (ONPs) possess great research interests for their promising effects in the enhancement of bioactivity including anticancer activity with less toxicity. The present study describes the preparation, characterization and biological evaluation of aqueous phase ONPs of potent 1,2-disubstituted benzimidazole derivative (BZ6) for anticancer activity. BZ6-ONPs were characterized through UV-absorption and fluorescence spectroscopic analysis for their photo-physical properties. DLS, TEM and SEM studies were carried out for morphological and structural analysis. Cytotoxicity determination on a panel of four different cancer cell lines (MCF-7, MiaPaca-2, HT-29 and HCT-116) revealed that the BZ6-ONPs show highest activity in human breast cancer MCF-7 cells. Surprisingly, the BZ6-ONPs were found to be non-toxic towards normal breast epithelial fR2 cells. Additionally, the FITC-ONPs showed enhanced uptake in 3D tumor spheroids of MCF-7 cells compared to the free FITC. BZ6-ONPs strongly halted cell proliferation and induced apoptosis, possibly through oxidative stress-mediated reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP) in MCF-7 cells. Moreover, molecular mechanism-based studies revealed that BZ6-ONPs downregulated AKT/NF-κB/vimentin/survivin-mediated oncogenic signaling pathway promoting cell proliferation and malignancy. In a nutshell, BZ6-ONPs are therapeutically efficacious, which needs further development as a treatment option in human mammary gland carcinomas.
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Bencimidazoles/química , Nanopartículas/química , Estrés Oxidativo , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , FN-kappa B/metabolismo , Nanopartículas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Esferoides Celulares/citología , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismoRESUMEN
The present work describes the synthesis, characterization, and anticancer properties of c(Lys-Pro), P1; c(Orn-Pro), P2; and conjugates PA-c(Lys-Pro), C1; PA-c(Orn-Pro), C2; EPA-c(Lys-Pro), C3; and EPA-c(Orn-Pro), C4. Among all, conjugate C4 displays potent anticancer activity with IC50 1.3 µM in MDA-MB-231, 3.5 µM in PC-3, 8.9 µM in MCF-7, and 9.6 µM in Miapaca-2 cancer cells. In addition, C4 downregulates the expression of MDM2 and abrogates the cancer cell invasion/metastasis. Through knock-down of MDM2, we demonstrate that this abrogation of metastasis by C4 is primarily MDM2 dependent. Furthermore, the animal studies underscore the antitumor as well as antimetastatic potential of C4 in vivo in breast cancer model at a safe and tolerable dose of 20 mg/kg.
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Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Metástasis de la Neoplasia/prevención & control , Péptidos Cíclicos/química , Péptidos Cíclicos/uso terapéutico , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Animales , Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/farmacología , Ácidos Grasos Insaturados/uso terapéutico , Femenino , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Metástasis de la Neoplasia/patología , Péptidos Cíclicos/farmacología , Proteínas Proto-Oncogénicas c-mdm2/genéticaRESUMEN
Induction of premature senescence represents a novel functional strategy to curb the uncontrolled proliferation of malignant cancer cells. This study unveils the regiospecific synthesis of novel isoxazoline derivatives condensed to ring A of medicinal plant product Withaferin-A. Intriguingly, the cis fused products with ß-oriented hydrogen exhibited excellent cytotoxic activities against proliferating human breast cancer MCF7 and colorectal cancer HCT-116 cells. The most potent derivative W-2b triggered premature senescence along with increase in senescence-associated ß-galactosidase activity, G2/M cell cycle arrest, and induction of senescence-specific marker p21Waf1/Cip1 at its sub-toxic concentration. W-2b conferred a robust increase in phosphorylation of mammalian checkpoint kinase-2 (Chk2) in cancer cells in a dose-dependent manner. Silencing of endogenous Chk2 by siRNA divulged that the amplification of p21 expression and senescence by W-2b was Chk2-dependent. Chk2 activation (either by ectopic overexpression or through treatment with W-2b) suppressed NM23-H1 signaling axis involved in cancer cell proliferation. Finally, W-2b showed excellent in vivo efficacy with 83.8% inhibition of tumor growth at a dose of 25 mg/kg, b.w. in mouse mammary carcinoma model. Our study claims that W-2b could be a potential candidate to limit aberrant cellular proliferation rendering promising improvement in the treatment regime in cancer patients.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Senescencia Celular/efectos de los fármacos , Isoxazoles/farmacología , Witanólidos/farmacología , Animales , Antineoplásicos/química , Apoptosis , Neoplasias de la Mama/metabolismo , Ciclo Celular , Proliferación Celular , Quinasa de Punto de Control 2/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Isoxazoles/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal , Células Tumorales Cultivadas , Witanólidos/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Multiple stresses are prevalent inside the tumor microenvironment rendering tumor growth, neighboring invasion and metastasis of the cancer cells to distant organs. NM23-H1 is the first metastasis suppressor gene identified and known to be implicated as an important regulator of stress-induced metastasis. Herein, we demonstrated that prototypical NM23-H1 expression diminished during hypoxia and serum starvation in Panc-1/MDA-MB-231 cells, but converse invasion patterns were obtained in these two diverse stresses. Supportingly, a compelling discrete difference in mRNA and protein levels of NM23-H1 was achieved in hypoxia as well as serum starvation. Knockdown of NM23-H1 activates EMT whereas the similar effects are subdued in serum starvation where NM23-H1 down-modulation prompted E-cadherin upregulation. Stable NM23-H1 expression augmented E-cadherin levels along with retardation in invadopodea formation and invasion. In hypoxia/serum starvation excess NM23-H1 effectively modulated the Twist1 promoter activity. Thus, differential regulation of NM23-H1 may corroborate/abrogate EMT depending on the nature of stress, tumor microenvironment and cellular context.
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Nucleósido Difosfato Quinasas NM23/metabolismo , Neoplasias/enzimología , Neoplasias/patología , Diferenciación Celular/fisiología , Hipoxia de la Célula/fisiología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Técnicas de Silenciamiento del Gen , Humanos , Células MCF-7 , Nucleósido Difosfato Quinasas NM23/genética , Metástasis de la Neoplasia , Neoplasias/genética , Transfección , Microambiente TumoralRESUMEN
Prostate apoptotic response 4 (Par-4) is coined as a therapeutic protein since owing to its diverse physiologically relevant properties, especially in the cancer perspective. Albeit, Par-4 expression is not restricted to any specific tissue/organ, apart from cell death promotion (due to challenging threats), the other biological role of Par-4 is convincingly emerging. In the recent years, several laboratories have intended to dissect the signaling or mechanisms involved in Par-4 activation to augment apoptosis cascades but new developments in Par-4 research have widened its therapeutic potential. One of these important avenues is the prevention of metastasis by pro-apoptotic Par-4. In this review, we will focus on the therapeutic perspective of Par-4 with a special reference to its (Par-4) virgin prospect of devastating metastasis control.