Osteopontin expression and its relationship with prognostic biomarkers in canine mammary carcinomas

ABSTRACT: Osteopontin is a glycophosphoprotein implicated in different physiologic and pathologic processes and is known to be involved in progression and metastasis of various cancers in humans, but this relation is still little explored in the veterinary. The aim was to evaluate the expression of osteopontin in canine mammary carcinomas and its relation with well-established canine mammary tumor biomarkers. For that, expression of OPN, EGFR, HER2, and c-Kit were evaluated along with Ki67 rate in 43 mammary carcinomas. Osteopontin was demonstrated to be expressed by neoplastic epithelial cells in all carcinomas as well as in stromal cells from the tumor microenvironment. Relation between high osteopontin expression and EGFR positivity (P<0.001) and HER2 overexpression (P=0.012) was demonstrated. In conclusion, high OPN expression seems to be related to poor prognosis and MAPK pathway activation, given the association with EGFR and HER2, members of the MAPK signaling pathway.

Download Full-text

p27kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1508514112 ◽

2015 ◽

Vol 112 (45) ◽

pp. 13916-13921 ◽

Cited By ~ 36

Author(s):

Linda Fabris ◽

Stefania Berton ◽

Ilenia Pellizzari ◽

Ilenia Segatto ◽

Sara D’Andrea ◽

...

Keyword(s):

Phase Transition ◽

Cell Cycle ◽

Signaling Pathway ◽

Mapk Pathway ◽

Mapk Signaling ◽

S Phase ◽

Point Of View ◽

Cell Cycle Entry ◽

Pathway Activation ◽

Direct Binding

The cyclin-dependent kinase (CDK) inhibitor p27kip1 is a critical regulator of the G1/S-phase transition of the cell cycle and also regulates microtubule (MT) stability. This latter function is exerted by modulating the activity of stathmin, an MT-destabilizing protein, and by direct binding to MTs. We recently demonstrated that increased proliferation in p27kip1-null mice is reverted by concomitant deletion of stathmin in p27kip1/stathmin double-KO mice, suggesting that a CDK-independent function of p27kip1 contributes to the control of cell proliferation. Whether the regulation of MT stability by p27kip1 impinges on signaling pathway activation and contributes to the decision to enter the cell cycle is largely unknown. Here, we report that faster cell cycle entry of p27kip1-null cells was impaired by the concomitant deletion of stathmin. Using gene expression profiling coupled with bioinformatic analyses, we show that p27kip1 and stathmin conjunctly control activation of the MAPK pathway. From a molecular point of view, we observed that p27kip1, by controlling MT stability, impinges on H-Ras trafficking and ubiquitination levels, eventually restraining its full activation. Our study identifies a regulatory axis controlling the G1/S-phase transition, relying on the regulation of MT stability by p27kip1 and finely controlling the spatiotemporal activation of the Ras-MAPK signaling pathway.

Download Full-text

Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer

eLife ◽

10.7554/elife.66524 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yusuke Inoue ◽

Ana Nikolic ◽

Dylan Farnsworth ◽

Rocky Shi ◽

Fraser D Johnson ◽

...

Keyword(s):

Lung Cancer ◽

Mapk Pathway ◽

Neuroendocrine Differentiation ◽

Therapy Resistance ◽

Mapk Signaling ◽

Chromatin Accessibility ◽

Extracellular Signal Regulated Kinase ◽

Pathway Activation ◽

Extracellular Signal ◽

Ets Factors

Small-cell lung cancer (SCLC) is neuroendocrine in origin and rarely contains mutations in the MAPK pathway. Likewise, non-SCLC (NSCLC) that transform to SCLC concomitantly with development of therapy resistance downregulate MAPK signaling, suggesting an inverse relationship between pathway activation and lineage state. To test this, we activated MAPK in SCLC through expression of mutant KRAS or EGFR, which revealed suppression of the neuroendocrine differentiation via ERK. We found that ERK induces expression of ETS factors that mediate transformation into a NSCLC-like state. ATAC-seq demonstrated ERK-driven changes in chromatin accessibility at putative regulatory regions and global chromatin rewiring at neuroendocrine and ETS transcriptional targets. Further, induction of ETS factors and suppression of neuroendocrine differentiation were dependent on histone acetyltransferases CBP/p300. Overall, we describe how the ERK-CBP/p300-ETS axis promotes a lineage shift between neuroendocrine and non-neuroendocrine phenotypes and provide rationale for the disruption of this program during transformation-driven resistance to targeted therapy.

Download Full-text

A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Cancers ◽

10.3390/cancers11101618 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1618 ◽

Cited By ~ 61

Author(s):

Braicu ◽

Buse ◽

Busuioc ◽

Drula ◽

Gulei ◽

...

Keyword(s):

Cancer Therapy ◽

Mapk Pathway ◽

Alternative Pathway ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Cancer Management ◽

Pathway Activation ◽

Promising Therapeutic Target ◽

Mitogen Activated Protein ◽

Mapk Inhibitors

The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.

Download Full-text

Antiprolactinoma Effect of Hordenine by Inhibiting MAPK Signaling Pathway Activation in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/3107290 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Xiong Wang ◽

Run-zhu Guo ◽

Li Ma ◽

Qiao-yan Ding ◽

Jun-hua Meng ◽

...

Keyword(s):

Pituitary Gland ◽

Signaling Pathway ◽

Mapk Pathway ◽

Interleukin 1 ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Mitogen Activated Protein Kinase ◽

Pathway Activation ◽

Mitogen Activated Protein ◽

Jnk Activation

Prolactinomas are harmful to human health, and the clinical first-line treatment drug is bromocriptine. However, 20% prolactinomas patients did not respond to bromocriptine. Hordenine is an alkaloid separated from Fructus Hordei Germinatus, which showed significant antihyperprolactinemia activity in rats. The aim of this study was to explore the effect and mechanism of hordenine on prolactinomas in rats. The study used estradiol to induce prolactinomas, which caused the activation of the pituitary mitogen-activated protein kinase (MAPK) pathway in rats significantly. The treatment of hordenine restored estradiol, induced the overgrowth of pituitary gland, and reduced the prolactin (PRL) accumulation in the serum and pituitary gland of rats by blocking the MAPK (p38, ERK1/2, and JNK) activation and production of inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). The antiprolactinoma effect of hordenine was mediated by inhibiting the MAPK signaling pathway activation in rats.

Download Full-text

Role of p38 MAPK pathway in apoptosis induction by saturated fatty acid in human pancreatic β-cells

Problems of Endocrinology ◽

10.14341/probl201662513-14 ◽

2016 ◽

Vol 62 (5) ◽

pp. 13-14

Author(s):

Jan Šrámek ◽

Vlasta Němcová-Fürstová ◽

Kamila Balušíková ◽

Petr Daniel ◽

Michael Jelínek ◽

...

Keyword(s):

Signaling Pathway ◽

P38 Mapk ◽

Mapk Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Erk Pathway ◽

Apoptosis Induction ◽

Β Cells ◽

Pancreatic Β Cells ◽

Pathway Activation

Background. Pancreatic β-cells failure and apoptosis in response to chronically elevated concentrations of saturated fatty acids in blood was considered as one of the main causes of type 2 diabetes mellitus development. Although precise molecular mechanisms of this process are still unclear, there are some indications that the p38 MAPK signaling pathway could be involved.Aim, materials and methods. Therefore, we tested the role of p38 MAPK signaling pathway activation in apoptosis induction by SA in human pancreatic β-cells NES2Y. Crosstalk between p38 MAPK pathway activation and accompanying ERK pathway inhibition after SA application was also tested.Results. We have found that saturated SA at apoptosis-inducing concentration (1 mM) activated the p38 MAPK signaling pathway MKK3/6→p38 MAPK→MAPKAPK-2 and inhibited the ERK signaling pathway c-Raf→MEK1/2→ERK1/2. The inhibition of p38 MAPK expression by siRNA silencing had no significant effect on cell viability or the level of phosphorylated ERK pathway members after SA administration. The inhibition of p38 MAPK activity by the specific inhibitor SB202190 resulted in noticeable activation of ERK pathway members after SA treatment but in no significant effect on cell viability. p38 MAPK overexpression by plasmid transfection produced no significant influence on cell viability or ERK pathway activation after SA exposure. The activation of p38 MAPK by the specific activator anisomycin led to apoptosis induction similar to application of SA (PARP cleavage and caspase-7, -8, and -9 activation) and in inhibition of ERK pathway members.Conclusions. We demonstrated that apoptosis-inducing concentrations of SA activate the p38 MAPK signaling pathway and that this activation could be involved in apoptosis induction by SA in the human pancreatic β-cells NES2Y. However, this involvement does not seem to play a key role. Crosstalk between p38 MAPK pathway activation and ERK pathway inhibition in NES2Y cells seems likely. Thus, the ERK pathway inhibition by p38 MAPK activation does not also seem to be essential for SA-induced apoptosis.

Download Full-text

Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors

Cancers ◽

10.3390/cancers13225757 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5757

Author(s):

Nada Tawfeeq ◽

Yonghao Jin ◽

Nazarius S. Lamango

Keyword(s):

Mapk Pathway ◽

A549 Cells ◽

Mapk Signaling ◽

Protein Signaling ◽

Ras Gtpases ◽

Anticancer Effects ◽

Pathway Activation ◽

Significant Difference ◽

Signaling Axis ◽

Anticancer Mechanism

Abnormalities of the MAPK pathway play vital roles in cancer initiation and progression. RAS GTPases that are key upstream mediators of the pathway are mutated in 30% of human cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed as potential targeted therapies against the RAS-driven cancers. The current study reports on the optimization of the PCAIs and the determination of their mechanisms of action in KRAS-mutant cancer cells. They display ClogP values ranging from 3.01 to 6.35, suppressing the viabilities of KRAS-mutant MDA-MB-231, A549, MIA PaCa-2, and NCI-H1299 cells in 2D and 3D cultures with EC50 values of 2.2 to 6.8, 2.2 to 7.6, 2.3 to 6.5 and 5.0 to 14 µM, respectively. When A549 cells were treated with the PCAIs, NSL-YHJ-2-27, for 48 h, no significant difference was observed in the levels of total or phosphorylated B- and C-Raf proteins. However, at 5 µM, it stimulated the phosphorylation of MEK1/2, ERK1/2, and p90RSK by 84%, 59%, and 160%, respectively, relative to controls. A non-farnesylated analog, NSL-YHJ-2-62, did not elicit similar effects. These data reveal that effects on the RAS-MAPK signaling axis most likely contribute to the anticancer effects of the PCAIs, possibly through the proapoptotic isoforms of p90RSK. The PCAIs may thus have the potential to serve the unmet therapeutic needs of patients with aberrant hyperactive G-protein signaling.

Download Full-text

Faculty Opinions recommendation of Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725301255.793502912 ◽

2015 ◽

Author(s):

Alex Toker ◽

Kristin Brown

Keyword(s):

Feedback Loop ◽

Mapk Pathway ◽

Human Cancer ◽

Pathway Activation

Download Full-text

Brassinin Inhibits Proliferation in Human Liver Cancer Cells via Mitochondrial Dysfunction

Cells ◽

10.3390/cells10020332 ◽

2021 ◽

Vol 10 (2) ◽

pp. 332

Author(s):

Taeyeon Hong ◽

Jiyeon Ham ◽

Jisoo Song ◽

Gwonhwa Song ◽

Whasun Lim

Keyword(s):

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Cell Lines ◽

Mapk Pathway ◽

Mapk Signaling ◽

Nuclear Antigen ◽

Cruciferous Vegetable ◽

Antiproliferative Effects ◽

Hep3b Cells ◽

Human Liver Cancer Cells

Brassinin is a phytochemical derived from Chinese cabbage, a cruciferous vegetable. Brassinin has shown anticancer effects on prostate and colon cancer cells, among others. However, its mechanisms and effects on hepatocellular carcinoma (HCC) have not been elucidated yet. Our results confirmed that brassinin exerted antiproliferative effects by reducing proliferating cell nuclear antigen (PCNA) activity, a proliferation indicator and inducing cell cycle arrest in human HCC (Huh7 and Hep3B) cells. Brassinin also increased mitochondrial Ca2+ levels and depolarized the mitochondrial membrane in both Huh7 and Hep3B cells. Moreover, brassinin generated high amounts of reactive oxygen species (ROS) in both cell lines. The ROS scavenger N-acetyl-L-cysteine (NAC) inhibited this brassinin-induced ROS production. Brassinin also regulated the AKT and mitogen-activated protein kinases (MAPK) signaling pathways in Huh7 and Hep3B cells. Furthermore, co-administering brassinin and pharmacological inhibitors for JNK, ERK1/2 and P38 decreased cell proliferation in both HCC cell lines more than the pharmacological inhibitors alone. Collectively, our results demonstrated that brassinin exerts antiproliferative effects via mitochondrial dysfunction and MAPK pathway regulation on HCC cells.

Download Full-text