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 Involvement of I-BAR protein IRSp53 in tumor cell growth via extracellular microvesicle secretion

2020 ◽  
Author(s):  
Hooi Ting Hu ◽  
Naoto Sasakura ◽  
Daisuke Matsubara ◽  
Naoko Furusawa ◽  
Masahiro Mukai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Culture Medium ◽  
Cellular Proliferation ◽  
Squamous Carcinoma ◽  
Mitogen Activated Protein Kinase ◽  
Mice Model ◽  
Bar Domain ◽  
Mitogen Activated Protein

AbstractCellular protrusions mediated by the membrane-deforming I-BAR domain protein IRSp53 are involved in cell migration, including metastasis. However, the role of IRSp53 in cell proliferation remains unclear. Here, we examined the role of IRSp53 in cell proliferation and found that it acts through secretion. Coculture of gingiva squamous carcinoma Ca9-22 cells and their IRSp53-knockout cells restored proliferation to parental Ca9-22 cell levels, suggesting possible secretion dependent on IRSp53. Notably, the amounts of microvesicle fraction proteins that were secreted into the culture medium were reduced in the IRSp53-knockout cells. The IRSp53-knockout cells exhibited decreased phosphorylation of mitogen-activated protein kinase, suggesting the decrease in the proliferation signals. The phosphorylation was restored by the addition of the microvesicles. In mice xenograft Ca9-22 cells, IRSp53-containing particles were secreted around the xenograft, indicating that IRSp53-dependent secretion occurs in vivo. In a tumor mice model, IRSp53 deficiency elongated lifespan. In some human cancers, the higher levels of IRSp53 mRNA expression was found to be correlated with shorter survival years. Therefore, IRSp53 is involved in tumor progression and secretion for cellular proliferation.

scholarly journals Transcriptional Repressor ERF Is a Ras/Mitogen-Activated Protein Kinase Target That Regulates Cellular Proliferation

1999 ◽  
Vol 19 (6) ◽  
pp. 4121-4133 ◽  
Author(s):  
Lionel le Gallic ◽  
Dionyssios Sgouras ◽  
Gregory Beal ◽  
George Mavrothalassitis
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Cellular Proliferation ◽  
Transcriptional Repressor ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Mitogen Activated Protein ◽  
Ets Family

ABSTRACT A limited number of transcription factors have been suggested to be regulated directly by Erks within the Ras/mitogen-activated protein kinase signaling pathway. In this paper we demonstrate that ERF, a ubiquitously expressed transcriptional repressor that belongs to the Ets family, is physically associated with and phosphorylated in vitro and in vivo by Erks. This phosphorylation determines the ERF subcellular localization. Upon mitogenic stimulation, ERF is immediately phosphorylated and exported to the cytoplasm. The export is blocked by specific Erk inhibitors and is abolished when residues undergoing phosphorylation are mutated to alanine. Upon growth factor deprivation, ERF is rapidly dephosphorylated and transported back into the nucleus. Phosphorylation-defective ERF mutations suppress Ras-induced tumorigenicity and arrest the cells at the G0/G1 phase of the cell cycle. Our findings strongly suggest that ERF may be important in the control of cellular proliferation during the G0/G1 transition and that it may be one of the effectors in the mammalian Ras signaling pathway.

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.

scholarly journals Evodiamine Induces Apoptosis in SMMC-7721 and HepG2 Cells by Suppressing NOD1 Signal Pathway

2018 ◽  
Vol 19 (11) ◽  
pp. 3419 ◽  
Author(s):  
Xing-Xian Guo ◽  
Xiao-Peng Li ◽  
Peng Zhou ◽  
Dan-Yang Li ◽  
Xiao-Ting Lyu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cellular Proliferation ◽  
Experimental Studies ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Signal Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Hcc Cells

Hepatocellular cancer (HCC) is a lethal malignancy with poor prognosis and easy recurrence. There are few agents with minor toxic side effects that can be used for treatment of HCC. Evodiamine (Evo), one of the major bioactive components derived from fructus Evodiae, has long been shown to exert anti-hepatocellular carcinoma activity by suppressing activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK). In addition, in the Nucleotide-Binding Oligomerization Domain 1 (NOD1) pathway, NOD1 could initiate NF-κB-dependent and MAPK-dependent gene transcription. Recent experimental studies reported that the NOD1 pathway was related to controlling development of various tumors. Here we hypothesize that Evo exerts anti-hepatocellular carcinoma activity by inhibiting NOD1 to suppress NF-κB and MAPK activation. Therefore, we proved the anti-hepatocellular carcinoma activity of Evo on HCC cells and detected the effect of Evo on the NOD1 pathway. We found that Evo significantly induced cell cycle arrest at the G2/M phase, upregulated P53 and Bcl-2 associated X proteins (Bax) proteins, and downregulated B-cell lymphoma-2 (Bcl-2), cyclinB1, and cdc2 proteins in HCC cells. In addition, Evo reduced levels of NOD1, p-P65, p-ERK, p-p38, and p-JNK, where the level of IκBα of HCC cells increased. Furthermore, NOD1 agonist γ-D-Glu-mDAP (IE-DAP) treatment weakened the effect of Evo on suppression of NF-κB and MAPK activation and cellular proliferation of HCC. In an in vivo subcutaneous xenograft model, Evo also exhibited excellent tumor inhibitory effects via the NOD1 signal pathway. Our results demonstrate that Evo could induce apoptosis remarkably and the inhibitory effect of Evo on HCC cells may be through suppressing the NOD1 signal pathway in vitro and in vivo.

scholarly journals p14–MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis

2006 ◽  
Vol 175 (6) ◽  
pp. 861-868 ◽  
Author(s):  
David Teis ◽  
Nicole Taub ◽  
Robert Kurzbauer ◽  
Diana Hilber ◽  
Mariana E. de Araujo ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Cellular Proliferation ◽  
Adaptor Protein ◽  
Tissue Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Complex ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Multicellular Organisms

The extracellular signal-regulated kinase (ERK) cascade regulates proliferation, differentiation, and survival in multicellular organisms. Scaffold proteins regulate intracellular signaling by providing critical spatial and temporal specificity. The scaffold protein MEK1 (mitogen-activated protein kinase and ERK kinase 1) partner (MP1) is localized to late endosomes by the adaptor protein p14. Using conditional gene disruption of p14 in mice, we now demonstrate that the p14–MP1-MEK1 signaling complex regulates late endosomal traffic and cellular proliferation. This function its essential for early embryogenesis and during tissue homeostasis, as revealed by epidermis-specific deletion of p14. These findings show that endosomal p14–MP1-MEK1 signaling has a specific and essential function in vivo and, therefore, indicate that regulation of late endosomal traffic by extracellular signals is required to maintain tissue homeostasis.

Ecdysone-inducible expression of oncogenic Ha-Ras in NIH 3T3 cells leads to transient nuclear localization of activated extracellular signal-regulated kinase regulated by mitogen-activated protein kinase phosphatase-1

2002 ◽  
Vol 362 (2) ◽  
pp. 305-315 ◽  
Author(s):  
David PLOWS ◽  
Paraskevi BRIASSOULI ◽  
Carolyn OWEN ◽  
Vassilis ZOUMPOURLIS ◽  
Michelle D. GARRETT ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Calcium Dependent ◽  
Transient Nature ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

The Ras family of GTP-binding proteins are key transducers of extracellular signals, particularly through the mitogen-activated protein kinase (MAPK) pathway. Constitutively active forms of Ras are found in a variety of tumours, suggesting an important role for this pathway in cancer. Here we report that initial cellular exposure to oncogenic Ras chronically activated the MAPK pathway in the cytoplasm, but transiently activated the same pathway in the nucleus. Nuclear-activated extracellular signal-regulated kinase (ERK) was rapidly dephosphorylated, with consequent short-term activation of the Elk-1 transcription factor and expression of the c-fos gene. Additional experiments suggested that the regulatory mechanism involved requires the calcium-dependent protein phosphotyrosine phosphatase MAPK phosphatase-1 (MKP-1). This is the first report on the ability of Ras, in the absence of growth factors, to transiently activate the MAPK pathway in the nucleus and show an involvement of MKP-1 in nuclear ERK2 regulation. In addition we show that transient activation of the MAPK pathway is sufficient to drive chronic cell-cycle progression. We conclude that, whereas the MAPK pathway is necessary to initiate cellular proliferation and transformation, the transient nature of the MAPK pathway activation suggests the involvement of additional signalling pathway(s) regulated by Ras.

scholarly journals LINC00978 promotes hepatocellular carcinoma carcinogenesis partly via activating the MAPK/ERK pathway

2020 ◽  
Vol 40 (3) ◽  
Author(s):  
Quan Zhang ◽  
Shujie Cheng ◽  
Liye Cao ◽  
Jihong Yang ◽  
Yu Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Mitogen Activated Protein Kinase ◽  
Erk Pathway ◽  
Western Blots ◽  
Cycle Progression

Abstract Objective: To study the role of long non-coding RNA (lncRNA) LINC00978 in hepatocellular carcinoma (HCC) carcinogenesis. Materials and methods: LINC00978 expression level was measured by reverse transcription quantitative real-time PCR (RT-qPCR) in HCC tissues and adjacent healthy liver tissues from 49 HCC patients. MTT assay, colony forming assay, and flow cytometry were performed to evaluate the effects of shRNA-mediated LINC00978 knockdown on HCC cell proliferation, cell cycle progression, and apoptosis in vitro. Xenograft tumor model was performed to determine the effects of LINC00978 knockdown on HCC tumor growth in vivo. Western blot was used to assess the activation of signaling molecules in the apoptosis and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Results: LINC00978 expression was significantly up-regulated in human HCC tissue relative to adjacent normal tissue, and LINC00978 high expression was correlated with poor HCC overall survival. LINC00978 was up-regulated in HCC cell lines. ShRNA-mediated LINC00978 knockdown significantly decreased HCC cell proliferation, and induced HCC cell cycle arrest and apoptosis in vitro. LINC00978 knockdown led to significant decrease in tumor xenograft size in vivo. Western blots revealed LINC00978 inhibition decreased ERK, p38, and c-Jun N-terminal kinase (JNK) phosphorylation in HCC cells. Conclusions: LINC00978 is highly expressed in human HCC tissue and correlates with poor HCC prognosis. LINC00978 promotes HCC cell proliferation, cell cycle progression, and survival, partially by activating the MAPK/ERK pathway. Our findings partially elucidated the roles of LINC00978 in HCC carcinogenesis, and identified a therapeutic target for HCC.

scholarly journals Long non-coding RNA HOMER3-AS1 drives hepatocellular carcinoma progression via modulating the behaviors of both tumor cells and macrophages

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Jian Pu ◽  
Wenchuan Li ◽  
Anmin Wang ◽  
Ya Zhang ◽  
Zebang Qin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Cells ◽  
Cellular Proliferation ◽  
Migration And Invasion ◽  
Downstream Target ◽  
Non Coding Rna ◽  
Cellular Apoptosis ◽  
Positive Correlations ◽  
Long Non Coding Rna

AbstractThe crosstalk between cancer cells and tumor microenvironment plays critical roles in hepatocellular carcinoma (HCC). The identification of long non-coding RNAs (lncRNAs) mediating the crosstalk might promote the development of new therapeutic strategies against HCC. Here, we identified a lncRNA, HOMER3-AS1, which is over-expressed in HCC and correlated with poor survival of HCC patients. HOMER3-AS1 promoted HCC cellular proliferation, migration, and invasion, and reduced HCC cellular apoptosis. Furthermore, HOMER3-AS1 promoted macrophages recruitment and M2-like polarization. In vivo, HOMER3-AS1 significantly facilitated HCC progression. Mechanism investigations revealed that HOMER3-AS1 activated Wnt/β-catenin signaling via upregulating HOMER3. Functional rescue experiments revealed that HOMER3/Wnt/β-catenin axis mediated the roles of HOMER3-AS1 in promoting HCC cellular malignant phenotypes. Furthermore, colony stimulating factor-1 (CSF-1) was also identified as a critical downstream target of HOMER3-AS1. HOMER3-AS1 increased CSF-1 expression and secretion. Blocking CSF-1 reversed the roles of HOMER3-AS1 in inducing macrophages recruitment and M2 polarization. Furthermore, positive correlations between HOMER3-AS1 and HOMER3 expression, HOMER3-AS1 and CSF-1 expression, and HOMER3-AS1 expression and M2-like macrophages infiltration were found in human HCC tissues. In summary, our findings demonstrated that HOMER3-AS1 drives HCC progression via modulating the behaviors of both tumor cells and macrophages, which are dependent on the activation of HOMER3/Wnt/β-catenin axis and CSF-1, respectively. HOMER3-AS1 might be a promising prognostic and therapeutic target for HCC.

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