scholarly journals The Jun N-terminal kinases signaling pathway plays a “seesaw” role in ovarian carcinoma: a molecular aspect

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Yingyu Dou ◽  
Xiaoyan Jiang ◽  
Hui Xie ◽  
Junyu He ◽  
Songshu Xiao
Keyword(s):  
Ovarian Cancer ◽  
Signaling Pathway ◽  
Driving Forces ◽  
Mapk Signaling ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Gynecological Malignancy ◽  
Mitogen Activated Protein ◽  
Jnk Inhibitors ◽  
Jnk Signaling Pathway

Abstract Ovarian cancer is the most common gynecological malignancy that causes cancer-related deaths in women today; this being the case, developing an understanding of ovarian cancer has become one of the major driving forces behind cancer research overall. Moreover, such research over the last 20 years has shown that the Jun N-terminal kinase (JNK) signaling pathway plays an important role in regulating cell death, survival, growth and proliferation in the mitogen-activated protein kinases (MAPK) signaling pathway, an important pathway in the formation of cancer. Furthermore, the JNK signaling pathway is often regulated by an abnormal activation in human tumors and is frequently reported in the literature for its effect on the progression of ovarian cancer. Although the FDA has approved some JNK inhibitors for melanoma, the agency has not approved JNK inhibitors for ovarian cancer. However, there are some experimental data on inhibitors and activators of the JNK signaling pathway in ovarian cancer, but related clinical trials need to be further improved. Although the Jun N-terminal kinase (JNK) signaling pathway is implicated in the formation of cancer in general, research has also indicated that it has a role in suppressing cancer as well. Here, we summarize this seemingly contradictory role of the JNK signaling pathway in ovarian cancer, that ‘seesaws’ between promoting and suppressing cancer, as well as summarizing the application of several JNK pathway inhibitors in cancer in general, and ovarian cancer in particular.

scholarly journals hCG Improves Luteal Function and Promotes Progesterone Output through the Activation of JNK Pathway in the Luteal Granulosa Cells of the Stimulated IVF Cycles†

2020 ◽  
Vol 102 (6) ◽  
pp. 1270-1280 ◽  
Author(s):  
Gamze Bildik ◽  
Nazli Akin ◽  
Yashar Esmaeilian ◽  
Francesko Hela ◽  
Kayhan Yakin ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Signaling Pathway ◽  
Granulosa Cells ◽  
Luteal Phase ◽  
Steroidogenic Enzymes ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Luteal Function ◽  
Jnk Signaling Pathway

Abstract Human chorionic gonadotropin (hCG) is a luteotropic hormone that promotes the survival and steroidogenic activity of corpus luteum (CL) by acting through luteinizing hormone receptors (LHRs) expressed on luteinized theca and granulosa cells (GCs). Therefore, it is used to support luteal phase in in vitro fertilization (IVF) cycles to improve clinical pregnancy rates and prevent miscarriage. However, the molecular mechanism underlying this action of hCG is not well characterized. To address this question, we designed an in vitro translational research study on the luteal GCs obtained from 58 IVF patients. hCG treatment at different concentrations and time points activated c-Jun N-terminal kinase (JNK) pathway and significantly increased its endogenous kinase activity along with upregulated expression of steroidogenic enzymes (steroidogenic acute regulatory protein (stAR), 3β-Hydroxysteroid dehydrogenase (3β-HSD)) in a dose-dependent manner in the luteal GCs. As a result, in vitro P production of the cells was significantly enhanced after hCG. When JNK pathway was inhibited pharmacologically or knocked-down with small interfering RNA luteal function was compromised, P4 production was declined along with the expression of stAR and 3β-HSD in the cells. Further, hCG treatment after JNK inhibition failed to correct the luteal defect and promote P4 output. Similar to hCG, luteinizing hormone (LH) treatment improved luteal function as well and this action of LH was associated with JNK activation in the luteal GCs. These findings could be important from the perspective of CL biology and luteal phase in human because we for the first time identify a critical role for JNK signaling pathway downstream LHR activation by hCG/LH in luteal GCs. Summary Sentence JNK signaling pathway plays a central role in the upregulated expression of the steroidogenic enzymes StAR and 3b-HSD and augmented progesterone production by hCG/LH in human luteal granulosa cells.

Effect of pharmacologic inhibition of c-Jun N-terminal kinase (JNK) signaling pathway on cell proliferation and cell cycle progression in human granulosa cell tumor.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22004-e22004
Author(s):  
Ozgur Oktem ◽  
Meltem Muftuoglu ◽  
Filiz Senbabaoglu ◽  
Bulent Urman
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Granulosa Cell ◽  
Dependent Manner ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Curative Therapy ◽  
Jnk Signaling Pathway ◽  
Dose Dependent

e22004 Background: No data are available regarding the signaling pathways that controls the proliferation of granulosa cell tumors (GCT). Preliminary findings showing the activation of c-Jun N-terminal kinase (JNK) signaling pathway in the proliferating granulosa cells has led us to investigate the role of this pathway in human GCT. Methods: Human GCT line COV 434 was used. Cell proliferation was monitored real-time quantitatively for 120h using an impedance-based system. Two different pharmacologic JNK inhibitors SP600125 and AS601245 were used. Their inhibitory concentrations were determined in western blot. Cell cycle was analyzed with flow cytometry and apoptosis with yo-pro-1 staining. Results: First, the growth characteristics of this cell line was delineated (Table 1A). Then the cells were treated with the inhibitors at the indicated doses during the log phase. Their proliferation was significantly halted in a dose-dependent manner by both inhibitors (Table 1B). Furthermore, the cells failed to complete mitosis, and began to accumulate at G2 in a dose dependent manner when JNK pathway was interrupted with AS601245 (59%) and SP600125 (39%) during G2/M transition compared to control cells (7%) proceeding through G2/M phase regularly (p<0.001). Compared to 3.5% of control cells, 14% and 30% of the cells underwent apoptosis when treated with 50 µM SP600125 and AS601245, respectively. At 100 µM, the apoptotic fraction increased to 68% and 76%, respectively (p<0.01). Conclusions: These results suggest that pharmacologic manipulation of JNK pathway may provide a therapeutic benefit in the treatment of GCT for which currently, no curative therapy exists beyond surgery. Funded by a Grant to Ozgur Oktem (TUBITAK109S164). [Table: see text]

scholarly journals Terminal differentiation of human granulosa cells as luteinization is reversed by activin-A through silencing of Jnk pathway

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Gamze Bildik ◽  
Nazli Akin ◽  
Yashar Esmaeilian ◽  
Francesko Hela ◽  
Ceren Sultan Yildiz ◽  
...  
Keyword(s):  
Corpus Luteum ◽  
Signaling Pathway ◽  
Granulosa Cells ◽  
Molecular Mechanisms ◽  
Terminal Differentiation ◽  
Reproductive Technologies ◽  
Activin A ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Jnk Signaling Pathway

Abstract Molecular mechanisms underlying luteinization (terminal differentiation of granulosa and theca cells after ovulation) and luteolysis (demise of corpus luteum) are poorly understood in human ovary. Here we report that activin-A, after binding to its cognate receptors induces a functional luteolytic state and reverses luteinization phenotype by downregulating the expression of the steroidogenic enzymes, LH receptor and VEGF and reducing estradiol (E2) progesterone (P4) production and upregulating FSH receptor and cyclin D1 expression in human primary luteinized granulosa cells. Further, this action of activin-A involves downregulation of JNK signaling pathway and is opposite to that of human chorionic gonadotropin (hCG), which acts as a luteotropic hormone and improves luteal function through the activation of JNK pathway in the same cell type. Reversal of luteinization phenotype in luteal granulosa cells by activin-A potentially makes this hormone an attractive candidate for use under certain clinical situations, where induction of luteolysis and rapid reduction of endogenous sex steroid levels are beneficial such as ovarian hyperstimulation syndrome (OHSS), in which the ovaries hyper-respond to gonadotropin stimulation by producing too many growing follicles along with development of ascites, pleural effusion, and hemo-concentrations as a result of increased vascular permeability and leakage of intravascular volume into third spaces. Our work unveils a previously undefined role for activin-A and JNK signaling pathway in human corpus luteum biology, that might have a direct clinical impact in assisted reproductive technologies.

Propranolol induced apoptosis and autophagy via the ROS/JNK signaling pathway in human ovarian cancer

2020 ◽  
Author(s):  
Shujun Zhao ◽  
Suzhen Fan ◽  
Yanyu Shi ◽  
Hongyan Ren ◽  
Hanqing Hong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Flow Cytometry ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Human Ovarian Cancer ◽  
Dependent Manner ◽  
Flow Cytometry Analysis ◽  
Jnk Signaling ◽  
Jnk Signaling Pathway ◽  
Induced Apoptosis

Abstract Background: Propranolol has a significant anti-cancer effect on various cancers. The present study aimed to investigate the underlying mechanism behind the therapeutic effect of Propranolol on the ovarian cancer.Materials and methods: The effect of Propranolol on cell viability was examined by MTT analysis. Cellular apoptosis was evaluated by flow cytometry analysis. Autophagy was defined by autophagosome observed by confocal microscopy after infected with GFP-LC3 adenovirus. In addition, the expression of marker proteins involved in cell apoptosis, autophagy, and ROS/JNK signaling pathway were estimated by Western Blotting assay.Results: Propranolol significantly reduced the viability of human ovarian cancer cell lines SKOV-3 and A2780 in a dose- and time-dependent manner. Flow cytometry analysis revealed that Propranolol induced the cell cycle arrest at G2/M phase and resulted in apoptosis. Moreover, autophagy inhibitor 3-MA markedly enhanced the Propranolol-induced apoptosis. In addition, reactive oxygen species (ROS) was demonstrated dramatically increased after Propranolol treatment and Propranolol activated the phosphorylation of JNK. What is more, p38 inhibitor SB203580 and JNK inhibitor SP600125 attenuated the upregulated expression of LC3-II and cleaved-caspase-3 by the effect of Propranolol. ROS exclusive inhibitor antioxidant N-acetyl cysteine (NAC) weaken the phosphorylation of JNK proteins induced by Propranolol.Conclusions：In summary, our results suggested that Propranolol induced cell apoptosis and protective autophagy through the ROS/JNK signaling pathway in human ovarian cancer cells.

scholarly journals Propranolol induced apoptosis and autophagy via the ROS/JNK signaling pathway in Human Ovarian Cancer

2020 ◽  
Vol 11 (20) ◽  
pp. 5900-5910
Author(s):  
Shujun Zhao ◽  
Suzhen Fan ◽  
Yanyu Shi ◽  
Hongyan Ren ◽  
Hanqing Hong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Signaling Pathway ◽  
Human Ovarian Cancer ◽  
Jnk Signaling ◽  
Jnk Signaling Pathway ◽  
Induced Apoptosis

scholarly journals LPS Cooperates with Poly-L-Arginine to Promote IL-6 and IL-8 Release via the JNK Signaling Pathway in NCI-H292 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Ling-Ling Zhang ◽  
Bing Chen ◽  
Xiao-Yun Fan ◽  
Sha-Sha Wu ◽  
Sheng-Quan Zhang ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Signaling Pathway ◽  
Enzyme Linked Immunosorbent Assay ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Time Points ◽  
Phosphorylation Level ◽  
Combined Use ◽  
Jnk Signaling Pathway ◽  
Lps Treatment

Objective. Herein, we aimed to study the mechanism whereby poly-L-arginine (PLA) and lipopolysaccharide (LPS) can synergistically induce the release of interleukin-6 (IL-6) and IL-8 in NCI-H292 cells.Methods. NCI-H292 cells were divided into control, PLA, LPS, and PLA+LPS groups. At various time points, the phosphorylation of JNK in each group was measured by western blotting. Additionally, the productions of IL-6 and IL-8 were assessed using an enzyme-linked immunosorbent assay (ELISA). The effects of SP600125, an inhibitor of the JNK pathway, on the increase of p-JNK, IL-6, and IL-8 were also studied.Results. Our results showed that either PLA or LPS treatment alone can significantly increase the phosphorylation level of JNK in NCI-H292 cells. Of interest was the combined use of PLA and LPS that has a synergistic effect on the phosphorylation of JNK, as well as synergistically inducing the release of IL-6 and IL-8 in NCI-H292 cells. Furthermore, SP600125 significantly inhibited the activation of JNK signal, as well as reducing the productions of IL-6 and IL-8 in response to PLA+LPS stimulation.Conclusions. The JNK signaling pathway contributes to the release of IL-6 and IL-8, which is stimulated by the synergistic actions of PLA+LPS in NCI-H292 cells.

scholarly journals ZPR1-Dependent Neurodegeneration Is Mediated by the JNK Signaling Pathway

2019 ◽  
Vol 13 ◽  
pp. 117906951986791 ◽  
Author(s):  
Xiaoting Jiang ◽  
Annapoorna Kannan ◽  
Laxman Gangwani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Signaling Pathway ◽  
Zinc Finger Protein ◽  
Muscular Atrophy ◽  
Gene Dosage ◽  
Mapk Signaling ◽  
Nuclear Accumulation ◽  
Neuron Degeneration ◽  
Jnk Signaling ◽  
Jnk Signaling Pathway

The zinc finger protein ZPR1 deficiency causes neurodegeneration and results in a mild spinal muscular atrophy (SMA)-like disease in mice with reduced Zpr1 gene dosage. Mutation of the survival motor neuron 1 ( SMN1) gene causes SMA. Spinal muscular atrophy is characterized by the degeneration of the spinal cord motor neurons caused by chronic low levels of SMN protein. ZPR1 interacts with SMN and is required for nuclear accumulation of SMN. Patients with SMA express reduced levels of ZPR1. Reduced Zpr1 gene dosage increases neurodegeneration and severity of SMA disease in mice. Mechanisms underlying ZPR1-dependent neurodegeneration are largely unknown. We report that neurodegeneration caused by ZPR1 deficiency is mediated by the c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPK). ZPR1-dependent neuron degeneration is mediated by central nervous system (CNS)-specific isoform JNK3. ZPR1 deficiency activates the MAPK signaling cascade, MLK3 → MKK7 → JNK3, which phosphorylates c-Jun and activates caspase-mediated neuron degeneration. Neurons from Jnk3-null mice show resistance to ZPR1-dependent neurodegeneration. Pharmacologic inhibition of JNK reduces degeneration of ZPR1-deficient neurons. These data show that ZPR1-dependent neurodegeneration is mediated by the JNK signaling pathway and suggest that ZPR1 downregulation in SMA may contribute to JNK-mediated neurodegeneration associated with SMA pathogenesis.

scholarly journals Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Kasmir Ramo ◽  
Koichi Sugamura ◽  
Siobhan Craige ◽  
John F Keaney ◽  
Roger J Davis
Keyword(s):  
Blood Flow ◽  
Signaling Pathway ◽  
Arterial Occlusion ◽  
Arterial Occlusive Disease ◽  
Occlusive Disease ◽  
Artery Ligation ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Collateral Arteries ◽  
Jnk Signaling Pathway

Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the formation of native collateral arteries that can restore circulation following arterial occlusion. Disruption of the MLK-JNK pathway causes decreased Dll4/Notch signaling, excessive sprouting angiogenesis, and defects in developmental vascular morphogenesis. Our analysis demonstrates that the MLK-JNK signaling pathway is a key regulatory mechanism that protects against ischemia in arterial occlusive disease.

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