scholarly journals Wild-Type p53 Attenuates Cancer Cell Motility by Inducing Growth Differentiation Factor-15 Expression

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 2987-2995 ◽  
Author(s):  
Jung-Chien Cheng ◽  
Hsun-Ming Chang ◽  
Peter C. K. Leung
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Cancer Cell ◽  
Cell Movement ◽  
Migration And Invasion ◽  
Wild Type ◽  
Growth Differentiation Factor 15 ◽  
Cancer Cell Motility ◽  
Differentiation Factor ◽  
Wild Type P53

A major function of the p53 tumor suppressor is the regulation of the cell cycle and apoptosis. In addition to its well-documented functions in malignant cancer cells, p53 can also regulate cell migration and invasion, which contribute to metastasis. Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, has been shown to be a downstream target of p53 and is associated with diverse human diseases and cancer progression. In this study, we examined the potential role of GDF-15 in p53-regulated cancer cell motility. We show that overexpression of wild-type p53 in two highly invasive p53-null human cancer cell lines, SKOV3 and PC3, attenuated cell migration and the movement through Matrigel. Using wild-type p53 and DNA-binding-deficient p53 mutants, we found that the transcriptional activity of p53 is required in the induction of GDF-15 expression. Cell movement through uncoated and Matrigel-coated transwell decreased in response to treatment with recombinant GDF-15, whereas the cell proliferation was not affected by GDF-15 treatment. Moreover, the induction of GDF-15 expression and secretion by p53 and the reduction in cell movement through Matrigel were diminished by treatment with GDF-15 small interfering RNA. This study demonstrates a mechanism by which p53 attenuates cancer cell motility through GDF-15 expression. In addition, our results indicate that GDF-15 mediates the functions of p53 by autocrine/paracrine action.

scholarly journals Moscatilin Inhibits Lung Cancer Cell Motility and Invasion via Suppression of Endogenous Reactive Oxygen Species

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Akkarawut Kowitdamrong ◽  
Pithi Chanvorachote ◽  
Boonchoo Sritularak ◽  
Varisa Pongrakhananon
Keyword(s):  
Lung Cancer ◽  
Reactive Oxygen Species ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Cell ◽  
Migration And Invasion ◽  
Oxygen Species ◽  
Lung Cancer Cell ◽  
Cancer Cell Motility ◽  
Endogenous Reactive Oxygen Species

Lung cancer is the leading cause of death among cancer patients worldwide, and most of them have died from metastasis. Migration and invasion are prerequisite processes associated with high metastasis potential in cancers. Moscatilin, a bibenzyl derivative isolated from the Thai orchidDendrobium pulchellum, has been shown to have anticancer effect against numerous cancer cell lines. However, little is known regarding the effect of moscatilin on cancer cell migration and invasion. The present study demonstrates that nontoxic concentrations of moscatilin were able to inhibit human nonsmall cell lung cancer H23 cell migration and invasion. The inhibitory effect of moscatilin was associated with an attenuation of endogenous reactive oxygen species (ROS), in which hydroxyl radical (OH∙) was identified as a dominant species in the suppression of filopodia formation. Western blot analysis also revealed that moscatilin downregulated activated focal adhesion kinase (phosphorylated FAK, Tyr 397) and activated ATP-dependent tyrosine kinase (phosphorylated Akt, Ser 473), whereas their parental counterparts were not detectable changed. In conclusion, our results indicate the novel molecular basis of moscalitin-inhibiting lung cancer cell motility and invasion and demonstrate a promising antimetastatic potential of such an agent for lung cancer therapy.

ARID1A interacts with nonmuscle myosin IIA to regulate cancer cell motility.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17036-e17036
Author(s):  
Oloruntoba Ismail Osagie ◽  
Zhigui Li ◽  
Shijun Mi ◽  
Jennifer T Aguilan ◽  
Gloria S. Huang
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Cell Lines ◽  
Cancer Cell ◽  
Protein Interaction ◽  
Protein Complex ◽  
Protein Identification ◽  
Cancer Cell Motility ◽  
Protein Protein Interaction ◽  
Myosin Iia

e17036 Background: ARID1A (BAF250A), a member of the SWI/SNF chromatin remodeling complex, is one of the most frequently mutated genes in human cancer. Here we report the discovery of a novel protein-protein interaction between ARID1A and the actin-binding motor protein, non-muscle myosin IIA (NM IIA) encoded by the myosin heavy chain 9 ( MYH9). Methods: The ARID1A immunoprecipitated protein complex was separated by gel electrophoresis followed by analysis of the peptide digested gel bands by C18-Reversed Phase chromatography using an Ultimate 3000 RSLCnano System (Thermo Scientific) equipped with an Acclaim PepMap C18 column (Thermo Scientific) and connected to a TriVersa NanoMate nanoelectrospray source (Advion) and a linear ion trap LTQ-XL mass spectrometer (Thermo Scientific). Protein identification was performed by Mascot search engine v. 2.5.1 (Matrix Science) against NCBI Homo sapiens database. Scaffold software v. 4.5.1 (Proteome Software Inc.) was used to validate the MS/MS peptide and protein identification based on 99% protein and 95% peptide probabilities. Immunoprecipitation and immunoblotting were done to evaluate the protein-protein interaction in ARID1A-wild type cell lines. Isogenic engineered cell lines, ES2 shRNA-control or shRNA- ARID1A stable transfection , and HCT116 control or ARID1A knockout by CRISPR-Cas9 (Horizon Discovery) were used to evaluate the effect of ARID1A loss on NM IIA expression and phosphorylation, and on cell migration by in vitro scratch assay with time lapse imaging. Results: Scaffold analysis of peptide spectra identified NM IIA with > 99% probability in the ARID1A immunopurified protein complex. In the ARID1A wildtype cell lines ES2 and KLE, endogenous NM IIA co-immunoprecipitated with ARID1A and vice versa. ES2 sh ARID1A cells had decreased total and phosphorylated NM IIA expression, and impaired cell migration compared to control cells. Similarly, HCT116 ARID1A homozygous knockout cells had impaired cell migration compared with HCT116 control cells. Conclusions: We report for the first time that ARID1A interacts with NM IIA to regulate cancer cell motility. Further investigation is ongoing to elucidate the significance of this newly identified function of ARID1A.

scholarly journals Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Sini K. Eerola ◽  
Niina M. Santio ◽  
Sanni Rinne ◽  
Petri Kouvonen ◽  
Garry L. Corthals ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Migration ◽  
Cancer Cell ◽  
Transcriptional Activity ◽  
Prostate Cancer Cell ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Wild Type ◽  
Pim Kinases ◽  
Target Sites

Abstract Background Progression of prostate cancer from benign local tumors to metastatic carcinomas is a multistep process. Here we have investigated the signaling pathways that support migration and invasion of prostate cancer cells, focusing on the role of the NFATC1 transcription factor and its post-translational modifications. We have previously identified NFATC1 as a substrate for the PIM1 kinase and shown that PIM1-dependent phosphorylation increases NFATC1 activity without affecting its subcellular localization. Both PIM kinases and NFATC1 have been reported to promote cancer cell migration, invasion and angiogenesis, but it has remained unclear whether the effects of NFATC1 are phosphorylation-dependent and which downstream targets are involved. Methods We used mass spectrometry to identify PIM1 phosphorylation target sites in NFATC1, and analysed their functional roles in three prostate cancer cell lines by comparing phosphodeficient mutants to wild-type NFATC1. We used luciferase assays to determine effects of phosphorylation on NFAT-dependent transcriptional activity, and migration and invasion assays to evaluate effects on cell motility. We also performed a microarray analysis to identify novel PIM1/NFATC1 targets, and validated one of them with both cellular expression analyses and in silico in clinical prostate cancer data sets. Results Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. We observed that also PIM2 and PIM3 can phosphorylate NFATC1, and identified several novel putative PIM1/NFATC1 target genes. These include the ITGA5 integrin, which is differentially expressed in the presence of wild-type versus phosphorylation-deficient NFATC1, and which is coexpressed with PIM1 and NFATC1 in clinical prostate cancer specimens. Conclusions Based on our data, phosphorylation of PIM1 target sites stimulates NFATC1 activity and enhances its ability to promote prostate cancer cell migration and invasion. Therefore, inhibition of the interplay between PIM kinases and NFATC1 may have therapeutic implications for patients with metastatic forms of cancer. Graphical abstract

scholarly journals Phosphorylated Osteopontin Secreted from Cancer Cells Induces Cancer Cell Motility

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1323
Author(s):  
Yoshinobu Kariya ◽  
Midori Oyama ◽  
Yukiko Kariya ◽  
Yasuhiro Hashimoto
Keyword(s):  
Cell Culture ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Culture Media ◽  
Cell Culture Media ◽  
Cancer Cell Motility ◽  
H460 Cells

Osteopontin (OPN) plays a pivotal role in cancer cell invasion and metastasis. Although OPN has a large number of phosphorylation sites, the functional significance of OPN phosphorylation in cancer cell motility remains unclear. In this study, we attempted to investigate whether phosphorylated OPN secreted from cancer cells affect cancer cell migration. Quantitative PCR and Western blot analyses revealed that MDA-MB435S, A549, and H460 cells highly expressed OPN, whereas the OPN expression levels in H358, MIAPaca-2, and Panc-1 cells were quite low or were not detected. Compared with the cancer cell lines with a low OPN expression, the high OPN-expressing cancer cell lines displayed a higher cell migration, and the cell migration was suppressed by the anti-OPN antibody. This was confirmed by the OPN overexpression in H358 cancer cells with a low endogenous OPN. Phos-tag ELISA showed that phosphorylated OPN was abundant in the cell culture media of A549 and H460 cells, but not in those of MDA-MB435S cells. Moreover, the A549 and H460 cell culture media, as well as the MDA-MB435S cell culture media with a kinase treatment increased cancer cell motility, both of which were abrogated by phosphatase treatment or anti-OPN antibodies. These results suggest that phosphorylated OPN secreted from cancer cells regulates cancer cell motility.

scholarly journals Phenyllactic acid promotes cell migration and invasion in cervical cancer via IKK/NF-κB-mediated MMP-9 activation

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Chao Li ◽  
Yanfei Li ◽  
Lanxia Sui ◽  
Jian Wang ◽  
Fang Li
Keyword(s):  
Cervical Cancer ◽  
Cell Motility ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Biological Function ◽  
Migration And Invasion ◽  
Phenyllactic Acid ◽  
Cancer Cell Motility ◽  
Invasive Behavior ◽  
Cervical Cancer Cells

Abstract Background Persistent infection with high-risk human papillomavirus (hrHPV) is associated with cervical cancer development. This process involves the virus-encoded E6 and E7 oncoproteins, which are maintained and expressed during all malignant transformation stages. However, HPV alone is insufficient to drive tumor progression-related behaviors such as cervical cancer cell motility. In this study, we investigated the effect of phenyllactic acid (PLA), a phenolic acid phytochemical and biomarker for discriminating various cancers, on the metastatic potential of cervical cancer cells. Methods The effects of PLA on HPV16/18 E6/E7 expression, migratory and invasive behavior, and matrix metalloproteinases (MMPs) expression of cervical cancers cells were measured. Specific inhibitors were used to further investigate biological function and underlying mechanism of PLA modulated cell motility. Results PLA significantly promoted the migration and invasion of SiHa, HeLa, and C-33A cervical cancer cells as well as upregulated matrix metalloproteinase-9 (MMP-9) expression. Moreover, PLA treatment attenuated E6/E7 expression in SiHa and HeLa cells. Further molecular analysis showed that PLA activated the nuclear factor-kappa B (NF-κB) signaling pathway and increased the nuclear translocation of both IκBα and p65. Treating cervical cancer cells with an NF-κB inhibitor potently reversed PLA-induced migratory and invasive behavior, MMP-9 upregulation, and/or E6/E7 downregulation. The PLA-induced NF-κB activation and MMP-9 upregulation were mediated by IκB kinase-β (IKK-β) phosphorylation via PKC signals. The results suggested that SiHa, HeLa, and C-33A cells might undergo a similar process to enhance their motility in response to PLA, regardless of the HPV status. Conclusions Collectively, our study reveals a new biological function of PLA and elucidate the possible molecular role of PLA as a risk factor for triggering cervical cancer cell motility.

scholarly journals Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism

2010 ◽  
Vol 190 (3) ◽  
pp. 461-477 ◽  
Author(s):  
Nao Hiramoto-Yamaki ◽  
Shingo Takeuchi ◽  
Shuhei Ueda ◽  
Kohei Harada ◽  
Satoshi Fujimoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Breast Cancer Cell Migration

EphA2, a member of the Eph receptor family, is frequently overexpressed in a variety of human cancers, including breast cancers, and promotes cancer cell motility and invasion independently of its ligand ephrin stimulation. In this study, we identify Ephexin4 as a guanine nucleotide exchange factor (GEF) for RhoG that interacts with EphA2 in breast cancer cells, and knockdown and rescue experiments show that Ephexin4 acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. The activation of RhoG recruits its effector ELMO2 and a Rac GEF Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells. In addition, the Dock4-mediated Rac activation is required for breast cancer cell migration. Our findings reveal a novel link between EphA2 and Rac activation that contributes to the cell motility and invasiveness of breast cancer cells.

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