Filamin A and Parafibromin Expression in Parathyroid Carcinoma

2021 ◽  
Author(s):  
Sara Storvall ◽  
Helena Leijon ◽  
Eeva M Ryhänen ◽  
Tiina Vesterinen ◽  
Ilkka Heiskanen ◽  
...  
Keyword(s):  
Parathyroid Carcinoma ◽  
Mitogen Activated Protein Kinase ◽  
Proliferation Index ◽  
Filamin A ◽  
Ki 67 ◽  
Mapk Signalling Pathway ◽  
Calcium Sensing ◽  
Mitogen Activated Protein ◽  
Benign Tumours ◽  
Parathyroid Tumours

Objective: Parathyroid carcinoma (PC), atypical parathyroid tumors (APT) and parathyroid adenoma (PA) present with hypercalcemia. Diminished calcium-sensing receptor (CaSR) expression is reported in PC but is rare in benign tumours. Filamin A (FLNA) binds to the CaSR and activates the mitogen-activated protein kinase (MAPK) signalling pathway. FLNA is related to tumour aggressiveness in several cancers, but its role in parathyroid neoplasia is unknown. Design: We examined FLNA, CaSR and parafibromin expression in PCs (n = 32), APTs (n = 44) and PAs (n = 77) and investigated their potential as diagnostic and/or prognostic markers. Methods: Tissue microarray slides were immunohistochemically stained with FLNA, CaSR and parafibromin. Staining results were correlated with detailed clinical data. Results: All tumours stained positively for CaSR, with two tumours (one PC and one APT) showing diminished expression. Carcinomas were characterized by increased cytoplasmic FLNA expression compared to APTs and PAs (p = 0.004). FLNA expression was not correlated with Ki-67 proliferation index or loss of parafibromin expression. Cytoplasmic FLNA expression was also associated with higher serum calcium, PTH concentrations and male sex (p = 0.014, p = 0.017 and p = 0.049, respectively). Using a combined marker score, we found that parathyroid tumours with low FLNA expression and positive parafibromin staining were extremely likely to be benign (p < 0.001). Conclusion: Cytoplasmic and membranous FLNA expression is increased in parathyroid carcinomas compared to benign tumours. A combined FLNA and parafibromin expression score shows potential as a prognostic predictor of indolent behaviour in parathyroid neoplasms.

Lupeol-Loaded Nanoparticles Enhance the Radiosensitivity of Hepatocellular Carcinoma by Inhibiting the Hyperactivation in Raf/Mitogen-Activated Protein Kinase and Phospatidylinositol-3 Kinase/mTOR Pathways

2021 ◽  
Vol 17 (11) ◽  
pp. 2247-2258
Author(s):  
Yinghai Xie ◽  
Changwei Liu ◽  
Shuping Zhou ◽  
Qi Wang ◽  
Xiaolong Tang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Mitogen Activated Protein Kinase ◽  
Proliferation Index ◽  
Nude Mouse Model ◽  
Ki 67 ◽  
Mitogen Activated Protein ◽  
Cellular Apoptosis

Radioresistance limits the effectiveness of radiotherapy for hepatocellular carcinoma. Raf and PI3K signaling cascades promote the formation of radioresistance in hepatocellular carcinoma (HCC). Lupeol has anticancer activity despite itspoor solubility in water and is toxic effect on normal tissue. In this study, nanoparticles (lupeol-NPs) were constructed using PEG-PLGA diblock copolymer vector, and results revealed that Lupeol-NPs reversed the radioresistance of hepatocellular carcinoma by inhibiting cellular proliferation and cell-cycle progression and promoting cellular apoptosis through blocking Raf/MAPK and PI3K/Akt signal transduction in radioresistant Huh-7R cells. In vivo, Lupeol-NPs combined with radiotherapy inhibited the growth of radioresistant hepatocellular carcinoma in a xenogenic nude mouse model. Ki-67 proliferation index decreased significantly (p < 0.05). We conclude that Lupeol-NPs can increase the sensitivity of radioresistant hepatocellular carcinoma to radiotherapy through inhibiting the Raf and PI3K signal cascades.

scholarly journals Effect of Novel Marine Nutraceuticals on IL-1α-Mediated TNF-αRelease from UVB-Irradiated Human Melanocyte-Derived Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Visalini Muthusamy ◽  
Lynn D. Hodges ◽  
Theodore A. Macrides ◽  
Glen M. Boyle ◽  
Terrence J. Piva
Keyword(s):  
Antioxidant Properties ◽  
Mitogen Activated Protein Kinase ◽  
Uvb Radiation ◽  
Reactive Oxygen Species Formation ◽  
Mapk Signalling Pathway ◽  
Species Formation ◽  
Human Melanocyte ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Necrosis Factor

UV-induced inflammation and reactive oxygen species formation are involved in the development of melanoma. Natural products like 5β-scymnol and CO2-supercritical fluid extract (CO2-SFE) of mussel oil contain anti-inflammatory and antioxidant properties that may aid in reducing the deleterious effects of UV radiation. Therefore, their effect on the release of the proinflammatory cytokine, tumour necrosis factor-α(TNF-α), from UVB-irradiated human melanocytic cells was examined. Human epidermal melanocytes (HEM) and MM96L melanoma cells were exposed to UVB radiation and IL-1α. Cell viability and TNF-αlevels were determined 24 hours after-irradiation while p38 mitogen-activated protein kinase (MAPK) activation was observed at 15 min after-irradiation. Whenα-tocopherol, CO2-SFE mussel oil, and 5β-scymnol were added to the UVB-irradiated HEM cells treated with IL-1α, TNF-αlevels fell by 53%, 65%, and 76%, respectively, while no inhibition was evident in MM96L cells. This effect was not due to inhibition of the intracellular p38 MAPK signalling pathway. These compounds may be useful in preventing inflammation-induced damage to normal melanocytes.

scholarly journals Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

2008 ◽  
Vol 26 (13) ◽  
pp. 2139-2146 ◽  
Author(s):  
Alex A. Adjei ◽  
Roger B. Cohen ◽  
Wilbur Franklin ◽  
Clive Morris ◽  
David Wilson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Phase Ii ◽  
Geometric Mean ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Type ◽  
Ki 67 ◽  
Phase Ii Studies ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.

Regulation of MAP kinase by calcium-sensing receptor in bovine parathyroid and CaR-transfected HEK293 cells

2001 ◽  
Vol 280 (2) ◽  
pp. F291-F302 ◽  
Author(s):  
Olga Kifor ◽  
R. John MacLeod ◽  
Ruben Diaz ◽  
Mei Bai ◽  
Toru Yamaguchi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Combined Treatment ◽  
Cell Types ◽  
Serine Phosphorylation ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Calcium Sensing ◽  
Cytosolic Phospholipase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Regulation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway by the extracellular calcium (Cao 2+)-sensing receptor (CaR) was investigated in bovine parathyroid and CaR-transfected human embryonic kidney (HEKCaR) cells. Elevating Cao 2+ or adding the selective CaR activator NPS R-467 elicited rapid, dose-dependent phosphorylation of ERK1/2. These phosphorylations were attenuated by pretreatment with pertussis toxin (PTX) or by treatment with the phosphotyrosine kinase (PTK) inhibitors genistein and herbimycin, the phosphatidylinositol-specific phospholipase C (PI-PLC) inhibitor U-73122, or the protein kinase C (PKC) inhibitor GF109203X and were enhanced by the PKC activator phorbol 12-myristate 13-acetate. Combined treatment with PTX and inhibitors of both PKC and PTK nearly abolished high Cao 2+-evoked ERK1/2 activation in HEKCaR cells, demonstrating CaR-mediated coupling via both Gq and Gi. High Cao 2+ increased serine phosphorylation of the 85-kDa cytosolic phospholipase A2(cPLA2) in both parathyroid and HEKCaR cells. The selective mitogen-activated protein kinase (MAPK) inhibitor PD98059 abolished high-Cao 2+-induced ERK1/2 activation and reduced cPLA2 phosphorylation in both cell types, documenting MAPK's role in cPLA2 activation. Thus our data suggest that the CaR activates MAPK through PKC, presumably through Gq/11-mediated activation of PI-PLC, as well as through Gi- and PTK-dependent pathway(s) in bovine parathyroid and HEKCaR cells and indicate the importance of MAPK in cPLA2 activation.

scholarly journals Inhibition of centrosome protein assembly leads to p53-dependent exit from the cell cycle

2006 ◽  
Vol 174 (5) ◽  
pp. 625-630 ◽  
Author(s):  
Vlastimil Srsen ◽  
Nicole Gnadt ◽  
Alexander Dammermann ◽  
Andreas Merdes
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
S Phase ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Antigen ◽  
Ki 67 ◽  
Mitogen Activated Protein ◽  
Centrosome Proteins ◽  
Centrosome Protein

Previous evidence has indicated that an intact centrosome is essential for cell cycle progress and that elimination of the centrosome or depletion of individual centrosome proteins prevents the entry into S phase. To investigate the molecular mechanisms of centrosome-dependent cell cycle progress, we performed RNA silencing experiments of two centrosome-associated proteins, pericentriolar material 1 (PCM-1) and pericentrin, in primary human fibroblasts. We found that cells depleted of PCM-1 or pericentrin show lower levels of markers for S phase and cell proliferation, including cyclin A, Ki-67, proliferating cell nuclear antigen, minichromosome maintenance deficient 3, and phosphorylated retinoblastoma protein. Also, the percentage of cells undergoing DNA replication was reduced by &gt;50%. At the same time, levels of p53 and p21 increased in these cells, and cells were predisposed to undergo senescence. Conversely, depletion of centrosome proteins in cells lacking p53 did not cause any cell cycle arrest. Inhibition of p38 mitogen-activated protein kinase rescued cell cycle activity after centrosome protein depletion, indicating that p53 is activated by the p38 stress pathway.

Sign in / Sign up

Export Citation Format

Share Document