Tomentodione M sensitizes multidrug resistant cancer cells by decreasing P-glycoprotein via inhibition of p38 MAPK signaling.
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ABSTRACT:
SUBMITTER: Zhou XW
PROVIDER: S-EPMC5731928 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aberrant androgen receptor (AR) signaling is a major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance in prostate cancer. Heat shock protein 27 (Hsp27) is a molecular chaperone that is activated in response to heat shock and hypoxia. Hsp27 has previously been reported to facilitate AR nuclear translocation in a p38 mitogen-activated protein kinase (MAPK) dependent manner in castration-sensitive prostate cancer cell lines. Here, we evaluated the potential for inhibiting p38 MAPK/Hsp27 mediated AR signaling under normoxia and hypoxia in experimental models of CRPC. We inhibited p38 MAPK with SB203580 in prostate cancer cell lines and measured Hsp27 phosphorylation, AR activity, cell proliferation, and clonogenicity under normoxia and hypoxia. AR activity was measured using an androgen response element driven reporter assay and qPCR to measure expression of AR target genes. Xenograft-bearing mice were treated with SB203580 to measure tumor growth and serum prostate specific antigen (PSA). Our results indicate that p38 MAPK and Hsp27 are activated under normoxia and hypoxia in response to androgens in CRPC cells. p38 MAPK inhibition diminished Hsp27 activation and the hypoxia-mediated increase in AR activity. Additionally, inhibition of p38 MAPK activity decreased proliferation and survival of CRPC cells in vitro and prolonged the survival of tumor-bearing mice. These results suggest that p38 MAPK inhibition may represent a therapeutic strategy to disrupt AR signaling in the heterogeneous CRPC tumor microenvironment.
| S-EPMC7922949 | biostudies-literature
Project description:p38 mitogen-activated protein kinases (MAPKs) respond to a wide range of extracellular stimuli. While the inhibition of p38 signaling is implicated in the impaired capacity to repair ultraviolet (UV)-induced DNA damage-a primary risk factor for human skin cancers-its mechanism of action in skin carcinogenesis remains unclear, as both anti-proliferative and survival functions have been previously described. In this study, we utilized cultured keratinocytes, murine tumorigenesis models, and human cutaneous squamous cell carcinoma (SCC) specimens to assess the effect of p38 in this regard. UV irradiation of normal human keratinocytes increased the expression of all four p38 isoforms (?/?/?/?); whereas irradiation of p53-deficient A431 keratinocytes derived from a human SCC selectively decreased p38?, without affecting other isoforms. p38? levels are decreased in the majority of human cutaneous SCCs assessed by tissue microarray, suggesting a tumor-suppressive effect of p38? in SCC pathogenesis. Genetic and pharmacological inhibition of p38? and in A431 cells increased cell proliferation, which was in turn associated with increases in NAPDH oxidase (NOX2) activity as well as intracellular reactive oxygen species (ROS). These changes led to enhanced invasiveness of A431 cells as assessed by the matrigel invasion assay. Chronic treatment of p53-/-/SKH-1 mice with the p38 inhibitor SB203580 accelerated UV-induced SCC carcinogenesis and increased the expression of NOX2. NOX2 knockdown suppressed the augmented growth of A431 xenografts treated with SB203580. These findings indicate that in the absence of p53, p38? deficiency drives SCC growth and progression that is associated with enhanced NOX2 expression and ROS formation.
| S-EPMC4019556 | biostudies-literature
Project description:Epilepsy is a chronic nervous system disease. Excessive increase of the excitatory neurotransmitter glutamate in the body results in an imbalance of neurotransmitters and excessive excitation of neurons, leading to epileptic seizures. Long‑term recurrent seizures lead to behavior and cognitive changes, and even increase the risk of death by 2‑ to 3‑fold relative to the general population. Adenosine A1 receptor (A1R), a member of the adenosine system, has notable anticonvulsant effects, and adenosine levels are controlled by the type 1 equilibrative nucleoside transporter (ENT1); in addition the p38 MAPK signaling pathway is involved in the regulation of ENT1, although the effect of its inhibitors on the expression levels of A1R and ENT1 is unclear. Therefore, in the present study, SB203580 was used to inhibit the p38 MAPK signaling pathway in rats, and the expression levels of A1R and ENT1 in the brain tissue of rats with acute LiCl‑pilocarpine‑induced status epilepticus was detected. SB203580 decreased pathological damage of hippocampal neurons, prolonged seizure latency, reduced the frequency of seizures, and decreased levels of A1R and ENT1 protein in rats.
| S-EPMC7647013 | biostudies-literature
Project description:BackgroundThe dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival. However, its role in leukemia is still unclear.MethodsWe exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIP-seq data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype.ResultsWe found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34+ cells. Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly, sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression.ConclusionsOur results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML.
| S-EPMC9178829 | biostudies-literature
Project description:The p38 mitogen-activated protein kinases (p38 MAPK) is a 38kD polypeptide recognized as the target for many potential anti-inflammatory agents. Accumulating evidence indicates that p38 MAPK could perform many roles in human disease pathophysiology. Therefore, great therapeutic benefits can be attained from p38 MAPK inhibitors. Ginseng is an exceptionally valued medicinal plant of the family Araliaceae (Panax genus). Recently, several studies targeted the therapeutic effects of purified individual ginsenoside, the most significant active ingredient of ginseng, and studied its particular molecular mechanism(s) of action rather than whole-plant extracts. Interestingly, several ginsenosides: ginsenosides compound K, F1, Rb1, Rb3, Rc, Rd, Re, Rf, Rg1, Rg2, Rg3, Rg5, Rh1, Rh2, Ro, notoginsenoside R1, and protopanaxadiol have shown to possess great therapeutic potentials mediated by their ability to downregulate p38 MAPK signaling in different cell lines and experimental animal models. Our review compiles the research findings of various ginsenosides as potent anti-inflammatory agents, highlighting the crucial role of p38 MAPK suppression in their pharmacological actions. In addition, in silico studies were conducted to explore the probable binding of these ginsenosides to p38 MAPK. The results obtained proposed p38 MAPK involvement in the beneficial pharmacological activities of ginsenosides in different ailments. Graphical abstract Image 1 Highlights • p38 MAPK plays many roles in human disease pathophysiology. Therefore, great therapeutic benefits can be attained from p38 MAPK inhibitors.• Several ginsenosides showed to possess great therapeutic potentials mediated by its ability to downregulate p38 MAPK signaling.• in silico studies were conducted to explore the binding of these ginsenosides to p38 MAPK and evidenced the promising their inhibitory effect. Ginsenosides; MAPK; apoptosis
| S-EPMC8605069 | biostudies-literature
Project description:Beta 2 glycoprotein I (?2GPI) has been shown the positive effect on diabetic atherosclerosis and retinal neovascularization. ?2GPI can be reduced by thioredoxin-1, resulting in the reduced state of ?2GPI. The possible protective effects of ?2GPI and reduced ?2GPI on diabetic nephropathy (DN) are not fully elucidated. The purpose of this study was to test a hypothesis that ?2GPI and reduced ?2GPI would improve DN in streptozotocin (STZ) induced diabetic mice and high-glucose (HG) exposed rat mesangial cell (RMC).The STZ-induced Balb/c mice and HG exposed RMCs were administrated with ?2-GPI and reduced ?2-GPI at different time and concentrations gradient respectively. The changes of glomerular structure and expression of collagen IV, TGF-?1, p38 MAPK and phospho-p38 MAPK in renal cortical and mesangial cells were observed by immunohistochemical techniques, quantitative real-time PCR and western blot with or without the treatment of ?2-GPI and reduced ?2-GPI.?2GPI and reduced ?2GPI improved early clinical and pathological changes of DN in STZ-diabetic mice. Treatment with ?2GPI and reduced ?2GPI in the STZ-diabetic mice and HG exposed RMCs resulted in decrease expression levels of TGF-?1 and collagen IV, with concomitant decrease in phospho-p38 MAPK expression.?2GPI and reduced ?2GPI improved renal structural damage and kidney function. The renoprotective and antifibrosis effects of ?2GPI and reduced ?2GPI on DN were closely associated with suppressing the activation of the TGF-?1-p38 MAPK pathway.
| S-EPMC4440048 | biostudies-literature
Project description:PURPOSE:Beta 2 glycoprotein I (?2GPI) has been shown the positive effect on diabetic atherosclerosis and retinal neovascularization. ?2GPI can be reduced by thioredoxin-1, resulting in the reduced state of ?2GPI. The possible protective effects of ?2GPI and reduced ?2GPI on diabetic nephropathy (DN) are not fully elucidated. The purpose of this study was to test a hypothesis that ?2GPI and reduced ?2GPI would improve DN in streptozotocin (STZ) induced diabetic mice and high-glucose (HG) exposed rat mesangial cell (RMC). METHODS:The STZ-induced Balb/c mice and HG exposed RMCs were administrated with ?2-GPI and reduced ?2-GPI at different time and concentrations gradient respectively. The changes of glomerular structure and expression of collagen IV, TGF-?1, p38 MAPK and phospho-p38 MAPK in renal cortical and mesangial cells were observed by immunohistochemical techniques, quantitative real-time PCR and western blot with or without the treatment of ?2-GPI and reduced ?2-GPI. RESULTS:?2GPI and reduced ?2GPI improved early clinical and pathological changes of DN in STZ-diabetic mice. Treatment with ?2GPI and reduced ?2GPI in the STZ-diabetic mice and HG exposed RMCs resulted in decrease expression levels of TGF-?1 and collagen IV, with concomitant decrease in phospho-p38 MAPK expression. CONCLUSIONS:?2GPI and reduced ?2GPI improved renal structural damage and kidney function. The renoprotective and antifibrosis effects of ?2GPI and reduced ?2GPI on DN were closely associated with suppressing the activation of the TGF-?1-p38 MAPK pathway.
| S-EPMC4509168 | biostudies-literature
Project description:The p38 MAPK pathway is an important regulator of many cellular responses. It is well established that p38 MAPK signalling negatively regulates epithelial cell transformation, but enhanced p38 MAPK activity has been also correlated with bad clinical prognosis in some tumour types. Here, we provide genetic and pharmacological evidence showing that p38 MAPK inhibition cooperates with the chemotherapeutic agent cisplatin to kill tumour cells. We show that p38 MAPK inhibition results in ROS upregulation, which in turn activates the JNK pathway via inactivation of phosphatases, sensitizing human tumour cells to cisplatin-induced apoptosis. Using a mouse model for breast cancer, we confirm that inhibition of p38 MAPK cooperates with cisplatin treatment to reduce tumour size and malignancy in vivo. Taken together, our results illustrate a new function of p38 MAPK that helps tumour cells to survive chemotherapeutic drug treatments, and reveal that the combination of p38 MAPK inhibitors with cisplatin can be potentially exploited for cancer therapy.
| S-EPMC3840490 | biostudies-literature
Project description:S100A11 is reported to associate with progression and poor prognosis in several tumors. We previously reported that S100A11 was highly expressed in intrahepatic cholangiocarcinoma (ICC) cells and promoted TGF-β1-induced EMT through SMAD2/3 signaling pathway. Here, we explored the prognostic role of S100A11 on ICC patients and preliminary molecular mechanisms how S100A11 regulated ICC cell proliferation. Our results showed that S100A11 was obviously increased in ICC tumor tissues. High expression of S100A11 was closely correlated with lymph node metastasis (LNM) and TNM stage and was an independent risk factor for patients' overall survival (OS) and recurrence-free survival (RFS). The nomograms comprising LNM and S100A11 achieved better predictive accuracy compared with TNM staging system for OS and RFS prediction. Silencing S100A11 significantly suppressed RBE cells and HCCC9810 cells proliferation, colony formation, and activation of P38/mitogen-activated protein kinase (MAPK) signaling pathway in vitro and inhibited tumor growth in vivo. In contrast, the overexpression of S100A11 in RBE cells and HCCC9810 cells achieved the opposite results. S100A11-induced proliferation was abolished after treatment with P38 inhibitor. Our findings suggest S100A11/P38/MAPK signaling pathway may be a potential therapeutic target for ICC patients.
| S-EPMC6587853 | biostudies-literature
Project description:To test the hypothesis that p38?-MAPK plays a critical role in the regulation of E3 ligase expression and skeletal muscle atrophy during unloading, we used VX-745, a selective p38? inhibitor. Three groups of rats were used: non-treated control (C), 3 days of unloading/hindlimb suspension (HS), and 3 days HS with VX-745 inhibitor (HSVX; 10 mg/kg/day). Total weight of soleus muscle in HS group was reduced compared to C (72.3 ± 2.5 vs 83.0 ± 3 mg, respectively), whereas muscle weight in the HSVX group was maintained (84.2 ± 5 mg). The expression of muscle RING-finger protein-1 (MuRF1) mRNA was significantly increased in the HS group (165%), but not in the HSVX group (127%), when compared with the C group. The expression of muscle-specific E3 ubiquitin ligases muscle atrophy F-box (MAFbx) mRNA was increased in both HS and HSVX groups (294% and 271%, respectively) when compared with C group. The expression of ubiquitin mRNA was significantly higher in the HS (423%) than in the C and HSVX (200%) groups. VX-745 treatment blocked unloading-induced upregulation of calpain-1 mRNA expression (HS: 120%; HSVX: 107%). These results indicate that p38?-MAPK signaling regulates MuRF1 but not MAFbx E3 ligase expression and inhibits skeletal muscle atrophy during early stages of unloading.
| S-EPMC7215762 | biostudies-literature