scholarly journals Protein Phosphatase 4 Promotes Hepatocyte Lipoapoptosis by Regulating RAC1/MLK3/JNK Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Xiuqing Huang ◽  
Guang Yang ◽  
Li Zhao ◽  
Huiping Yuan ◽  
Hao Chen ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Hepatic Insulin Resistance ◽  
Jnk Pathway ◽  
Pathway Activation ◽  
Jnk Signaling Pathway ◽  
Induced Apoptosis ◽  
Jnk Activation ◽  
First Time

Lipotoxicity-induced apoptosis, also referred to as lipoapoptosis, is one of the important initial factors promoting the progression from hepatosteatosis to nonalcoholic steatohepatitis (NASH). Saturated free fatty acids (SFAs), which are increased significantly in NASH, are directly hepatotoxic which induce hepatocyte lipoapoptosis. Previously, we reported that protein phosphatase 4 (PP4) was a novel regulator of hepatic insulin resistance and lipid metabolism, but its role in hepatic lipoapoptosis remains unexplored. In this study, we found out that PP4 was upregulated in the livers of western diet-fed-induced NASH mice and SFA-treated murine primary hepatocytes and HepG2 cells. In addition, we found for the first time that suppression of PP4 decreased SFA-induced JNK activation and expression of key modulators of hepatocyte lipoapoptosis including p53-upregulated modulator of apoptosis (PUMA) and Bcl-2-interacting mediator (Bim) and reduced hepatocyte lipoapoptosis level as well both in vitro and in vivo. Further study revealed that PP4 induced JNK activation and lipoapoptosis-related protein expression by regulating the RAC1/MLK3 pathway instead of the PERK/CHOP pathway. The effects of palmitate-treated and PP4-induced lipoapoptosis pathway activation were largely abolished by RAC1 inhibition. Moreover, we identified that PP4 interacted with RAC1 and regulated GTPase activity of RAC1. In conclusion, these results demonstrated that PP4 was a novel regulator of hepatocyte lipoapoptosis and mediated hepatocyte lipoapoptosis by regulating the RAC1/MLK3/JNK signaling pathway. Our finding provided new insights into the mechanisms of this process.

scholarly journals Berberine Induces NSCLC Apoptosis Via Activation of ROS/ASK1/JNK Pathway in Vitro and Vivo

2021 ◽  
Author(s):  
qianqian chen ◽  
Yaqin Hou ◽  
Bingjie Hao ◽  
Zhou Ding ◽  
Qing Xia ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Cell Counting ◽  
Ros Generation ◽  
Dependent Manner ◽  
Jnk Pathway ◽  
Mitochondrial Membrane Depolarization ◽  
Induced Apoptosis ◽  
Jnk Activation

Abstract BackgroundNon-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Berberine (BBR), as an isoquinoline alkaloid, is commonly utilized in traditional Chinese medicine. Previous studies have proven that BBR possesses potential anti-tumor effect. However, the mechanism of on mitochondrial function in anti-NSCLC are still unknown.MethodsCell Counting Kit-8 (CCK-8), flow cytometry and western blotting were utilized to characterize the roles and relationships among BBR, ROS, ASK1, JNK, coxIV,caspase-3, cytochrome c ,bcl-2 and bax in NSCLC. Immunohistochemical (IHC) analysis was built to examine their expression in vivo.ResultsIn this study, we found that BBR potently suppressed NSCLC cells (A549 and PC9) growth by inducing apoptosis in a dose- and time-dependent manner. BBR induced apoptosis in NSCLC as evidenced by caspase-3 cleavage, cytochrome c release, and mitochondrial membrane depolarization. Furthermore, BBR induced ROS generation and ASK1 and JNK activation. To explore whether such apoptosis was linked to ROS production and ASK1 and JNK activation, we treated cells with a JNK inhibitor (SP600125), which significantly suppressed BBR-induced apoptosis. We further found that treating these cells with the anti-oxidant N-acetyl cysteine (NAC) was sufficient to both suppress ASK1 and JNK activation and to disrupt apoptotic induction.ConclusionsTogether, these data suggest that BBR induces NSCLC cells apoptosis via ROS-mediated ASK1/JNK and mitochondrial pathway activation.

scholarly journals Loss offlflTriggers JNK-Dependent Cell Death inDrosophila

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Jiuhong Huang ◽  
Lei Xue
Keyword(s):  
Cell Death ◽  
Function Analysis ◽  
Ectopic Expression ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Jnk Pathway ◽  
Dependent Cell ◽  
Jnk Activation ◽  
First Time

falafel(flfl) encodes aDrosophilahomolog of human SMEK whosein vivofunctions remain elusive. In this study, we performed gain-of-function and loss-of-function analysis inDrosophilaand identified flfl as a negative regulator of JNK pathway-mediated cell death. While ectopic expression offlflsuppresses TNF-triggered JNK-dependent cell death, loss offlflpromotes JNK activation and cell death in the developing eye and wing. These data report for the first time an essential physiological function offlflin maintaining tissue homeostasis and organ development. As the JNK signaling pathway has been evolutionary conserved from fly to human, a similar role of PP4R3 in JNK-mediated physiological process is speculated.

scholarly journals PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Shuiping Liu ◽  
Haoming Lin ◽  
Da Wang ◽  
Qiang Li ◽  
Hong Luo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Clinical Success ◽  
Dominant Role ◽  
Autophagic Cell Death ◽  
Jnk Activation ◽  
First Time ◽  
The Relationship

Abstract5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.

scholarly journals DAB2IP predicts treatment response and prognosis of ESCC patients and modulates its radiosensitivity through enhancing IR-induced activation of the ASK1-JNK pathway

2020 ◽  
Author(s):  
Yue Li ◽  
Meng Xu ◽  
Weiyang Fang ◽  
Lei Sheng ◽  
Xiangcun Chen ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Jnk Pathway ◽  
Interacting Protein ◽  
Molecular Etiology ◽  
Jnk Signaling Pathway ◽  
Underlying Mechanisms ◽  
And Function ◽  
Crt Response

Abstract BACKGROUND: Disabled homolog 2 interacting protein (DAB2IP) plays a tumor-suppressive role in several types of human cancers. However, the molecular status and function of the DAB2IP gene in esophageal squamous cell carcinoma (ESCC) is rarely reported. METHODS: We examined the expression dynamics of DAB2IP by immunohistochemistry (IHC) in 140 ESCC patients treated with definite chemoradiotherapy. A series of in vivo and in vitro experiments were performed to elucidate the effect of DAB2IP on the chemoradiotherapy (CRT) response and its underlying mechanisms in ESCC.RESULTS: Decreased expression of DAB2IP in ESCCs correlated positively with ESCC resistance to CRT and was a strong and independent predictor for short disease-specific survival (DSS) of ESCC patients. Furthermore, the therapeutic sensitivity of CRT was substantially increased by ectopic overexpression of DAB2IP in ESCC cells. In addition, knockdown of DAB2IP dramatically enhanced resistance to CRT in ESCC. Finally, we demonstrated that DAB2IP regulates ESCC cell radiosensitivity through enhancing ionizing radiation (IR)-induced activation of the ASK1-JNK signaling pathway.CONCLUSIONS: Our data highlight the molecular etiology and clinical significance of DAB2IP in ESCC, which may represent a new therapeutic strategy to improve therapy and survival for ESCC patients.

scholarly journals Isoliquiritigenin Suppresses E2-Induced Uterine Leiomyoma Growth through the Modulation of Cell Death Program and the Repression of ECM Accumulation

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1131 ◽  
Author(s):  
Po-Han Lin ◽  
Hsiang-Lin Kung ◽  
Hsin-Yuan Chen ◽  
Ko-Chieh Huang ◽  
Shih-Min Hsia
Keyword(s):  
Cell Death ◽  
Uterine Leiomyoma ◽  
Reproductive Age ◽  
Cell Cycles ◽  
Cell Death Program ◽  
Associated Proteins ◽  
Induced Apoptosis ◽  
Jnk Activation

Uterine leiomyomas, also known as fibroids, are common and prevalent in women of reproductive age. In this study, the effect of Isoliquiritigenin (ISL), a licorice flavonoid, on the anti-proliferation of uterine leiomyoma was investigated. We found that the survival of uterine leiomyoma ELT3 cells and primary uterine smooth muscle (UtSMC) cells was reduced by treatment with ISL alone or with ISL plus estradiol (E2). Cell cycles were arrested through the reduction of G2/M- and S-phase populations in ELT3 and UtSMC cells, respectively. Furthermore, increased sub-G1 phase and nucleus condensation were observed in ELT3 cells but not in UtSMC cells. Co-treatment of ELT3 cells with E2 and ISL inhibited ERK1/2 activation, whereas p38 and c-Jun N-terminal kinase (JNK) activation was enhanced. Moreover, ISL-induced apoptosis and autophagy cell death in ELT3 cells were observed. Serum E2 and P4 levels were reduced in a E2-enhanced uterine myometrium hyperplasia mouse model by ISL treatment, which contributed to the downregulation of the expression of extracellular matrix (ECM) associated proteins and matrix metalloproteinase (MMPs). Taken together, these results showed that ISL exerted a higher effect on the inhibition of estrogen-induced uterine leiomyoma growth for both in vitro and in vivo ECM accumulation, demonstrating its potential as a new option for treatment of uterine leiomyoma.

c-Jun N-Terminal Kinase (JNK) Activation Failure Confers a New Mechanism of Anthracycline Resistance in Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2377-2377
Author(s):  
Eleni D. Lagadinou ◽  
Panagiotis G. Ziros ◽  
Olga A. Tsopra ◽  
Kostas Dimas ◽  
Panagiotis Pantazis ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Fold Increase ◽  
U937 Cells ◽  
Jnk Pathway ◽  
Empty Vector ◽  
Anthracycline Resistance ◽  
Induced Apoptosis ◽  
Jnk Activation ◽  
Acute Myeloid

Abstract Chemotherapy resistance remains a major challenge in the treatment of acute myeloid leukemia (AML). Besides the P-glycoprotein efflux of chemotherapeutics, additional cellular factors may contribute to drug resistance in AML. c- Jun N-terminal Kinase (JNK) is a protein kinase activated after exposure of cells to chemotherapeutic agents. Recently, studies in solid tumours have associated chemoresistance with failure of cancer cells to activate JNK. We asked whether drug resistance in AML is also attributed to intrinsic failure of the AML blasts to activate JNK. In vitro treatment of U937 AML cell line with anthracyclines induced a rapid and robust JNK phosphorylation and apoptosis. In contrast, the anthracyline-resistant derivative U937R cells showed no JNK activation after exposure to anthracyclines, also at doses that resulted in high accumulation of the drug within the cells. Inhibition of JNK in drug-sensitive U937 cells made them resistant to anthracyclines. First, JNK1-siRNA transfected U937 cells exhibited a 50.4% and 61.3% reduced daunorubicin- (DNR, 1μM 24hr) and doxorubicin- (DOX, 1.5 μM 24hr) induced apoptosis respectively; as compared to empty vector or untransfected U937 cells (P< 0.001). Second, pretreatment of U937 cells with the 420116 cell-permeable JNK inhibitor (1 μM) reduced to a less but yet significant extent DNR-induced apoptosis as compared to cells treated with a negative control peptide (P = 0.013<0.05). On the other hand, selective restoration of the inactive JNK pathway in resistant U937R cells by transfection with a mutant form of the SEK1/MKK4 upstream activator of JNK sensitized U937R cells to anthracyclines, compared to empty vector transfected cells (3.3-fold increase in DNR-induced apoptosis, 1μM DNR, 24hr and 3.1-fold increase in DOX-induced apoptosis, 1.5μM DOX, 24hr). Furthermore, we assessed the activation of JNK pathway in 29 primary AML bone marrow samples after short term (30-60 min) in vitro exposure to DNR (1 μM) and correlated it with clinical data. We found a strong correlation between the in vitro pharmacodymanic changes of phospho-JNK levels in AML primary blasts and the response of the AML patients to standard induction chemotherapy (P = 0.012). In addition, the drug-induced JNK activation pattern correlated with AML evolving from antecedent MDS (P = 0.017) and patient age (P = 0.046). In summary, our in vitro and in vivo results suggest that JNK activation failure is another mechanism of anthracycline resistance in AML. Elucidating the ultimate mechanisms leading to JNK suppression in chemoresistant AML may be of major therapeutic value.

Combining RAD001 (Everolimus) with Proteasome Inhibitors Bortezomib (Velcade) or MG132 Significantly Enhances Pre-B ALL Cell Death in Vitro.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2743-2743
Author(s):  
Philip O. Saunders ◽  
Kenneth F Bradstock ◽  
Linda J. Bendall
Keyword(s):  
Cell Death ◽  
Lymphoblastic Leukemia ◽  
Significant Proportion ◽  
Receptor Activation ◽  
Jnk Pathway ◽  
Dna Damaging Agents ◽  
Pathway Activation ◽  
Wide Range ◽  
Jnk Activation

Abstract Abstract 2743 Poster Board II-719 Mammalian target of rapamycin (mTOR) inhibitors have shown potential as novel therapeutic agents with efficacy against a wide range of tumors including precursor-B acute lymphoblastic leukemia (pre-B ALL). We have previously reported RAD001 (16μM) induces JNK pathway activation in pre-B ALL cells and that combining RAD001 with DNA damaging agents in vitro significantly enhanced JNK dependent death, via a caspase dependent mechanism. We sought to evaluate agents, which may favor JNK activation and promote JNK dependent cell death in pre-B ALL cells. Bortezomib and MG132 have both been reported to activate the JNK pathway via death receptor activation, with reported efficacy in pre-B ALL. Consistent with the literature we observed enhanced JNK pathway activation in pre-B ALL cells treated with bortezomib. Analysis of annexin V and 7AAD expression by flow cytometry utilizing JNK inhibitor SP600125 (5μM) showed that a significant proportion of pre-B ALL cell death observed with bortezomib was JNK dependent. Combining RAD001 (4–16μM) with bortezomib in vitro (10–20nM) significantly enhanced cell death in pre-B ALL cell lines and patient cases at 24 hours. This observation was supported by equivalent observations combining MG132 (250–500nM) with RAD001 (8–16μM). The degree of enhanced killing was greater than that achieved combining RAD001 (16μM) with DNA damaging agents. Enhanced killing was also achieved at a significantly lower dose of RAD001 relative to combination therapy with DNA damage. Utilizing JNK inhibitor SP600125 (5μM) we determined that a significant proportion of enhanced killing was JNK dependent. In conclusion we have identified two novel and clinically available agents which when combined can significantly enhance pre-B ALL cell death. Our observations suggest combining agents which induce JNK activation has the potential to enhance clinical responses in pre-B ALL, particularly for patients with advanced or relapsed disease, for whom treatment with cytotoxic chemotherapy offers little hope of improved survival. In vivo studies will provide further insight into this promising strategy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Sulforaphane Inhibits Osteoclastogenesis via Suppression of the Autophagic Pathway

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 347
Author(s):  
Tingting Luo ◽  
Xiazhou Fu ◽  
Yaoli Liu ◽  
Yaoting Ji ◽  
Zhengjun Shang
Keyword(s):  
Bone Destruction ◽  
Control Group ◽  
Tartrate Resistant Acid Phosphatase ◽  
Transmission Electron ◽  
Jnk Signaling Pathway ◽  
First Time ◽  
Autophagic Proteins

Previous studies have demonstrated that sulforaphane (SFN) is a promising agent against osteoclastic bone destruction. However, the mechanism underlying its anti-osteoclastogenic activity is still unclear. Herein, for the first time, we explored the potential role of autophagy in SFN-mediated anti-osteoclastogenesis in vitro and in vivo. We established an osteoclastogenesis model using receptor activator of nuclear factor kappa-β ligand (RANKL)-induced RAW264.7 cells and bone marrow macrophages (BMMs). Tartrate-resistant acid phosphatase (TRAP) staining showed the formation of osteoclasts. We observed autophagosomes by transmission electron microscopy (TEM). In vitro, we found that SFN inhibited osteoclastogenesis (number of osteoclasts: 22.67 ± 0.88 in the SFN (0) group vs. 20.33 ± 1.45 in the SFN (1 μM) group vs. 13.00 ± 1.00 in the SFN (2.5 μM) group vs. 6.66 ± 1.20 in the SFN (2.5 μM) group), decreased the number of autophagosomes, and suppressed the accumulation of several autophagic proteins in osteoclast precursors. The activation of autophagy by rapamycin (RAP) almost reversed the SFN-elicited anti-osteoclastogenesis (number of osteoclasts: 22.67 ± 0.88 in the control group vs. 13.00 ± 1.00 in the SFN group vs. 17.33 ± 0.33 in the SFN+RAP group). Furthermore, Western blot (WB) analysis revealed that SFN inhibited the phosphorylation of c-Jun N-terminal kinase (JNK). The JNK activator anisomycin significantly promoted autophagy, whereas the inhibitor SP600125 markedly suppressed autophagic activation in pre-osteoclasts. Microcomputed tomography (CT), immunohistochemistry (IHC), and immunofluorescence (IF) were used to analyze the results in vivo. Consistent with the in vitro results, we found that the administration of SFN could decrease the number of osteoclasts and the expression of autophagic light chain 3 (LC3) and protect against lipopolysaccharide (LPS)-induced calvarial erosion. Our findings highlight autophagy as a crucial mechanism of SFN-mediated anti-osteoclastogenesis and show that the JNK signaling pathway participates in this process.

scholarly journals Core erythropoietin receptor signals for late erythroblast development

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2662-2672 ◽  
Author(s):  
Madhu P. Menon ◽  
Jing Fang ◽  
Don M. Wojchowski
Keyword(s):  
Erythropoietin Receptor ◽  
Kinase Activation ◽  
P70s6 Kinase ◽  
Action Mechanisms ◽  
Site Restoration ◽  
Jnk Activation ◽  
First Time ◽  
Reticulocyte Production

AbstractCritical signals for erythroblast formation are transduced by activated, tyrosine-phosphorylated erythropoietin receptor (EpoR) complexes. Nonetheless, steady-state erythropoiesis is supported effectively by EpoR alleles that are deficient in cytoplasmic phosphotyrosine sites. To better define core EpoR action mechanisms, signaling capacities of minimal PY-null (EpoR-HM) and PY343-retaining (EpoR-H) alleles were analyzed for the first time in bone marrow–derived erythroblasts. Jak2 activation via each allele was comparable. Stat5 (and several Stat5-response genes) were induced via EpoR-H but not via EpoR-HM. Stat1 and Stat3 activation was nominal for all EpoR forms. For both EpoR-HM and EpoR-H, Akt and p70S6-kinase activation was decreased multifold, and JNK activation was minimal. ERKs, however, were hyperactivated uniquely via EpoR-HM. In vivo, Epo expression in EpoR-HM mice was elevated, while Epo-induced reticulocyte production was diminished. In vitro, EpoR-HM erythroblast maturation also was attenuated (based on DNA content, forward-angle light scatter, and hemoglobinization). These EpoR-HM–specific defects were corrected not only upon PY343 site restoration in EpoR-H, but also upon MEK1,2 inhibition. Core EpoR PY site-independent signals for erythroblast formation therefore appear to be Stat5, Stat1, Stat3, p70S6-kinase, and JNK independent, but ERK dependent. Wild-type signaling capacities, however, depend further upon signals provided via an EpoR/PY343/Stat5 axis.

scholarly journals Glibenclamide induces apoptosis by activating reactive oxygen species dependent JNK pathway in hepatocellular carcinoma cells

2017 ◽  
Vol 37 (5) ◽  
Author(s):  
Bin Yan ◽  
Zhiyong Peng ◽  
Xiao Xing ◽  
Chunling Du
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Jnk Pathway ◽  
Cycle Arrest ◽  
Pathway Activation ◽  
Huh7 Cells ◽  
M Phase ◽  
Induced Apoptosis ◽  
Jnk Activation ◽  
Hcc Cells

Glibenclamide (Gli) is a widely employed drug in the treatment of type 2 diabetes and many lines of evidence have described its anti-tumor effects in some neoplasms. The aim of the present study was to investigate the effect of Gli on apoptosis of human hepatocellular carcinoma (HCC) cells and to analyze the underlying pathway involved in this action. Two HCC cell lines, HepG-2 and Huh7 were used as the cell models. We found that Gli treatment significantly inhibited cell viability, induced a significant cell-cycle arrest in G2/M-phase and induced apoptosis in both HepG-2 and Huh7 cells. We further verified that apoptosis induction by Gli was accompanied by increase in ROS levels and activation of the JNK pathway. Scavenging of the intracellular ROS with its blocker N-acetyl-L-cysteine (NAC) could mitigate the Gli-induced apoptosis and JNK activation in the two HCC cell lines. Furthermore, inhibition of JNK pathway by its inhibitor SP100625 effectively reduced Gli-induced apoptosis in HCC cells. In conclusion, Gli treatment significantly induced cell apoptosis by promoting ROS-dependent JNK pathway activation in HCC cells. Gli may be a potential clinical anti-tumor drug for HCC.

Sign in / Sign up

Export Citation Format

Share Document