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1.
Cell Biosci ; 12(1): 119, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35908024

RESUMO

BACKGROUND: Developmental signaling pathways such as those of Hedgehog (HH) and WNT play critical roles in cancer stem cell self-renewal, migration, and differentiation. They are often constitutively activated in many human malignancies, including non-small cell lung cancer (NSCLC). Previously, we reported that two oxysterol derivatives, Oxy186 and Oxy210, are potent inhibitors of HH/GLI signaling and NSCLC cancer cell growth. In addition, we also showed that Oxy210 is a potent inhibitor of TGF-ß/SMAD signaling. In this follow-up study, we further explore the mechanism of action by which these oxysterols control NSCLC cell proliferation and tumor growth. RESULTS: Using a GLI-responsive luciferase reporter assay, we show here that HH ligand could not mount a signaling response in the NSCLC cell line A549, even though Oxy186 and Oxy210 still inhibited non-canonical GLI activity and suppressed the proliferation of A549 cells. Further, we uncover an unexpected activity of these two oxysterols in inhibiting the WNT/ß-catenin signaling at the level of LRP5/6 membrane receptors. We also show that in a subcutaneous xenograft tumor model generated from A549 cells, Oxy186, but not Oxy210, exhibits strong inhibition of tumor growth. Subsequent RNA-seq analysis of the xenograft tumor tissue reveal that the WNT/ß-catenin pathway is the target of Oxy186 in vivo. CONCLUSION: The oxysterols Oxy186 and Oxy210 both possess inhibitory activity towards WNT/ß-catenin signaling, and Oxy186 is also a potent inhibitor of NSCLC tumor growth.

2.
J Korean Acad Nurs ; 51(3): 334-346, 2021 Jun.
Artigo em Coreano | MEDLINE | ID: mdl-34215711

RESUMO

PURPOSE: The purpose of this study was to develop a resilience enhancement program applying mindfulness meditation (REP-MM) and evaluate the effects of the program on post-traumatic stress (PTS), resilience, and health-related quality of life (HRQoL) in patients with ileostomy. METHODS: The REP-MM was developed by combining the resilience enhancement program with mindfulness meditation according to four patterns. The program was developed through identifying patients' needs, reviewing relevant literature, developing a preliminary program, and testing content validity and user evaluation. The participants were 55 patients with ileostomy. We conveniently assigned 27 patients to the experimental group and 28 to the control group. The study was conducted in conducted in a hospital from January 22 to May 30, 2019. The REPMM was provided to the experimental group, and conventional ileostomy care was provided to the control group using a nonequivalent control-group pretest-posttest design. RESULTS: ANCOVA revealed that the levels of PTS (F = 321.64, p < .001), resilience (F = 111.86, p < .001), and HRQoL (F = 31.08, p < .001) in the experimental group were higher than those in the control group when comparing pretest to posttest changes. CONCLUSION: The REP-MM is effective in PTS, resilience, and HRQoL in patients suffering from post-stoma creation crisis. The REP-MM can induce positive self-recognition changes in patients with ileostomy through dispositional, situational, relational, and philosophical interventions. We suggest nurses reduce PTS and improve resilience and HRQoL in patients with ileostomy.


Assuntos
Ileostomia/psicologia , Meditação , Atenção Plena , Qualidade de Vida/psicologia , Resiliência Psicológica , Depressão , Humanos , Avaliação de Programas e Projetos de Saúde , Transtornos de Estresse Pós-Traumáticos
3.
Cell Death Dis ; 10(10): 689, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534138

RESUMO

The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention.


Assuntos
Oxirredutases do Álcool/genética , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética/genética , Feminino , Humanos
4.
Oncogene ; 38(17): 3185-3200, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30626936

RESUMO

Transforming growth factor-ß (TGF-ß) is major inducer of epithelial-to-mesenchymal transition (EMT), which associates with cancer cell metastasis and resistance to chemotherapy and targeted drugs, through both transcriptional and non-transcriptional mechanisms. We previously reported that, in cancer cells, heightened mitogenic signaling allows TGF-ß-activated Smad3 to interact with poly(RC) binding protein 1 (PCBP1) and together they regulate many alternative splicing events that favors expression of protein isoforms essential for EMT, cytoskeletal rearrangement, and adherens junction signaling. Here we show that the exclusion of TGF-ß-activated kinase 1 (TAK1) variable exon 12 requires another RNA-binding protein, Fox-1 homolog 2 (Rbfox2), which binds intronic sequences in front of exon 12 independently of the Smad3-PCBP1 complex. Functionally, exon 12-excluded TAK1∆E12 and full-length TAK1FL are distinct. The short isoform TAK1∆E12 is constitutively active and supports TGF-ß-induced EMT and nuclear factor kappa B (NF-κB) signaling, whereas the full-length isoform TAK1FL promotes TGF-ß-induced apoptosis. These observations offer a harmonious explanation for how a single TAK1 kinase can mediate the opposing responses of cell survival and apoptosis in response to TGF-ß. They also reveal a propensity of the alternatively spliced TAK1 isoform TAK1∆E12 to cause drug resistance due to its activity in supporting EMT and NF-κB survival signaling.


Assuntos
Processamento Alternativo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , MAP Quinase Quinase Quinases/genética , Fator de Crescimento Transformador beta/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Humanos , Camundongos , Fosforilação/genética , Isoformas de Proteínas/genética , Proteínas Repressoras/genética , Transdução de Sinais/genética , Proteína Smad3/genética , Transcrição Gênica/genética
5.
Cancer Sci ; 108(9): 1769-1777, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28699254

RESUMO

ß-Catenin is a central player in Wnt signaling, and activation of Wnt signaling is associated with cancer development. E-cadherin in complex with ß-catenin mediates cell-cell adhesion, which suppresses ß-catenin-dependent Wnt signaling. Recently, a tumor-suppressive role for E-cadherin has been reconsidered, as re-expression of E-cadherin was reported to enhance the metastatic potential of malignant tumors. To explore the role of E-cadherin, we established an E-cadherin-expressing cell line, EC96, from AGS cells that featured undetectable E-cadherin expression and a high level of Wnt signaling. In EC96 cells, E-cadherin re-expression enhanced cell proliferation, although Wnt signaling activity was reduced. Subsequent analysis revealed that nuclear factor-κB (NF-κB) activation and consequent c-myc expression might be involved in E-cadherin expression-mediated cell proliferation. To facilitate rapid proliferation, EC96 cells enhance glucose uptake and produce ATP using both mitochondria oxidative phosphorylation and glycolysis, whereas AGS cells use these mechanisms less efficiently. These events appeared to be mediated by NF-κB activation. Therefore, E-cadherin re-expression and subsequent induction of NF-κB signaling likely enhance energy production and cell proliferation.


Assuntos
Caderinas/metabolismo , Metabolismo Energético , NF-kappa B/metabolismo , Antígenos CD , Caderinas/genética , Linhagem Celular Tumoral , Proliferação de Células , Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Humanos , Via de Sinalização Wnt
6.
Exp Cell Res ; 340(1): 12-21, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26704260

RESUMO

Many recent studies have revealed that axin is involved in numerous cellular functions beyond the negative regulation of ß-catenin-dependent Wnt signaling. Previously, an association of ectopic axin with mitochondria was observed. In an effort to investigate the relationship between axin and mitochondria, we found that axin expression suppressed cellular ATP production, which was more apparent as axin expression levels increased. Also, mitochondrial expression of axin was observed using two axin-expressing HeLa cell models: doxycycline-inducible ectopic axin expression (HeLa-axin) and axin expression enhanced by long-term treatment with XAV939 (HeLa-XAV). In biochemical analysis, axin is associated with oxidative phosphorylation (OXPHOS) complex IV and is involved in defects in the assembly of complex IV-containing supercomplexes. Functionally, axin expression reduced the activity of OXPHOS complex IV and the oxygen consumption rate (OCR), suggesting axin-mediated mitochondrial dysfunction. Subsequent studies using various inhibitors of Wnt signaling showed that the reduction in cellular ATP levels was weaker in cases of ICAT protein expression and treatment with iCRT3 or NSC668036 compared with XAV939 treatment, suggesting that XAV939 treatment affects ATP synthesis in addition to suppressing Wnt signaling activity. Axin-mediated regulation of mitochondrial function may be an additional mechanism to Wnt signaling for regulation of cell growth.


Assuntos
Trifosfato de Adenosina/biossíntese , Proteína Axina/genética , Proteína Axina/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Trifosfato de Adenosina/metabolismo , Proliferação de Células/efeitos dos fármacos , Doxiciclina/farmacologia , Células HeLa , Humanos , Mitocôndrias/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real
7.
Apoptosis ; 19(4): 657-67, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24287941

RESUMO

Axin is a multifunctional protein that participates in many cellular events including Wnt signaling and cell fate determination. Aurora kinase inhibitor (AKI)-induced cell death and cell membrane rupture is facilitated in L929 cells expressing axin (L-axin cells) through the activation of poly ADP-ribose polymerase (PARP). We observed that caspase-2 activity is required for AKI-induced cell death. Inhibition of caspase-2 activity suppressed AKI-induced PARP activation and mitochondrial dysfunction, resulting in a decrease in AKI-induced cell death. When an axin mutant deleted for the glycogen synthase kinase 3ß (GSK3ß)-binding domain was expressed in L929 cells (L-ΔGSK cells), AKI-induced caspase-2 activation and cell death decreased. AKI treatment reduced the expression of a 32-kDa caspase-2 splicing variant (caspase-2S) in most L-axin cells, but not in L-ΔGSK cells. These results suggest that AKI-induced caspase-2 activation in L-axin cells might be due to a decrease in the expression of caspase-2S, which inhibits caspase-2 activity. In addition, AKI treatment failed to activate caspase-8 and treatment with necrostatin inhibited AKI-induced cell death in L-axin cells, suggesting that the absence of caspase-8 activation might favor necrotic cell death. Axin expression may facilitate AKI-induced caspase-2 activation followed by activation of PARP and initiation of the necrotic cell death pathway.


Assuntos
Aurora Quinases/antagonistas & inibidores , Proteína Axina/metabolismo , Caspase 2/metabolismo , Animais , Aurora Quinases/metabolismo , Caspase 8/metabolismo , Inibidores de Caspase/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Ativação Enzimática , Camundongos , Necrose , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo
8.
Exp Cell Res ; 318(16): 2022-33, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22742926

RESUMO

Cytoplasmic axin expression frequently produces punctuate structures in cells, but the nature of axin puncta has not been fully elucidated. In an effort to analyze cytoplasmic axin puncta, we established HeLa cells expressing axin in a doxycycline-inducible manner (HeLa-Axin). We observed that axin accumulated in an aggregate-like pattern in perinuclear areas and appeared to be associated with mitochondria, Golgi apparatus, and endoplasmic reticulum (ER), but not lysosomes. Further biochemical analysis suggested that some part of the cytoplasmic axin pool was associated with mitochondria. In addition, mitochondrial proteins [i.e., cytochrome oxidase IV (CoxIV) and cytochrome c] were slightly higher in HeLa-Axin cells than in HeLa-EV cells, suggesting altered mitochondrial degradation. HeLa-Axin cells were then treated with staurosporine (STS) to determine if the mitochondria-induced apoptosis pathway was altered. Compared to STS-treated control cells (HeLa-EV), HeLa-Axin cells had less STS-induced cytotoxicity and reduced caspase-3 activation and PARP cleavage. Given that mitochondria outer membrane potential was unchanged, HeLa-Axin cells might be relatively resistant to STS-mediated mitochondrial damage. Mitochondria associated with axin aggregates were resistant to detergent-mediated permeabilization. These results suggest that axin forms aggregate-like structures in association with mitochondria, which render mitochondria resistant to STS-induced membrane damage and cytotoxicity.


Assuntos
Proteína Axina/genética , Inibidores Enzimáticos/farmacologia , Mitocôndrias/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estaurosporina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteína Axina/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Expressão Gênica , Células HeLa , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Ligação Proteica , Transdução de Sinais/genética
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