Phorbol ester-induced migration of HepG2 cells is accompanied by intensive stress fibre formation, enhanced integrin expression and transient down-regulation of p21-activated kinase 1

Gujdár, Annamária; Sipeki, Szabolcs; Bander, Erzsébet; Buday, László; Farago, Anna F.

doi:10.1016/s0898-6568(02)00087-6

Cited by 18 publications

(11 citation statements)

References 41 publications

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“…The inhibition of DNA synthesis results in an accumulation of cells in the G1 phase of the cell cycle. Similar results have been described for the parent cell line of C3A, HepG2 (15). In addition, we demonstrate here that TPA increases glucose uptake in C3A cells.…”

Section: Discussionsupporting

confidence: 91%

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Regulation of de novo phosphatidylinositol synthesis

Nuwayhid

Vega

Walden

et al. 2006

Journal of Lipid Research

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Mechanisms that function to regulate the rate of de novo phosphatidylinositol (PtdIns) synthesis in mammalian cells have not been elucidated. In this study, we characterize the effect of phorbol ester treatment on de novo PtdIns synthesis in C3A human hepatoma cells. Incubation of cells with 12-O-tetradecanoyl phorbol 13-acetate (TPA) initially (1-6 h) results in a decrease in precursor incorporation into PtdIns; however, at later times (18-24 h), a marked increase is observed. TPA-induced glucose uptake from the medium is not required for observation of the stimulation of PtdIns synthesis, because the effect is apparent in glucose-free medium. Inhibition of the activation of arachidonic acid substantially blocks the synthesis of PtdIns but has no effect on the synthesis of phosphatidylcholine (PtdCho). Increasing the concentration of cellular phosphatidic acid by blocking its conversion to diacylglycerol, on the other hand, enhances the synthesis of PtdIns and inhibits the synthesis of PtdCho. The TPA-induced stimulation of PtdIns synthesis is not the result of the concomitant TPA-induced G1 arrest, because G1 arrest induced by mevastatin has no effect on PtdIns synthesis. Inhibition of protein kinase C activity blocks the stimulatory action of TPA on de novo synthesis of PtdIns but has no effect on TPA-induced inhibition.Potential sites of enzymatic regulation are discussed.-Nuwayhid, S. J., M. Vega, P. D. Walden, and M. E. Monaco. Phosphatidylinositol (PtdIns) is an essential acidic phospholipid found in the membranes of mammalian cells (1) as well as on the chromatin (2). A single molecular species composed of stearate (R9) and arachidonate (R99) accounts for z80% of the total PtdIns. There are two pathways for the synthesis of PtdIns: the de novo pathway and the salvage pathway, which converge at the level of phosphatidic acid (PtdOH). The de novo pathway uses dihydroxyacetone phosphate derived from glucose to make glycerol phosphate, which is subsequently acylated at the sn-1 position with stearate and then at the sn-2 position with arachidonate to yield PtdOH. In the salvage pathway, diacylglycerol (DAG), derived from phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP 2 ), is converted to PtdOH through the action of DAG kinase. In the first instance, there is a net increase in PtdIns, whereas in the second, there is not. The central element of both pathways is the production of PtdOH. For the salvage pathway, it appears that the conversion of DAG to PtdOH by DAG kinase is stimulated as a result of agonist-induced polyphosphoinositide turnover. Whether this results from an increase in DAG substrate and/or an increase in DAG kinase enzyme activity is unclear. This laboratory has previously demonstrated that the two pathways can be differentiated in situ on the basis of the inhibition by triacsin C, a specific inhibitor of arachidonate-specific long-chain fatty acyl-CoA synthetase (ACSL4) in situ (3, 4).Although regulation of the salvage pathway via the activation ...

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Section: Discussionsupporting

confidence: 91%

“…It has been reported that TPA causes growth inhibition, migration, and G1 arrest in HepG2 cells, the parent line of C3A (15)(16)(17). Similar findings apply to C3A cells.…”

Section: Effect Of G1 Arrest On Ptdins Synthesissupporting

confidence: 68%

Regulation of de novo phosphatidylinositol synthesis

Nuwayhid

Vega

Walden

et al. 2006

Journal of Lipid Research

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“…The actin stress fiber formation is considered a characteristic feature for cell migration through the cytoskeletal architecture remodeling. 36,37 Our finding may thus suggest that PFTK1 translated protein, hPFTAIRE1, confers cellular motility on HCC cells via the modulation of filamentous actin dynamics. The effect of PFTK1 on WEE1, an inhibitory protein on the Cdc2/cyclin complex formation, was also investigated.…”

Section: Discussionmentioning

confidence: 76%

Identification ofPFTAIREprotein kinase 1, a novel cell division cycle-2 related gene, in the motile phenotype of hepatocellular carcinoma cells

Pang

Bai

et al. 2007

Hepatology

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Metastasis is a major cause of cancer morbidity and mortality in individuals with hepatocellular carcinoma (HCC), yet little is known about the underlying molecular basis. Using genetic information derived from chromosome-based comparative genomic hybridization, we have reported previously on regional chromosome 7q21-q22 gains in close association with HCC progression. In this study, we undertook cDNA microarray-based comparative genomic hybridization, to examine the 7q21-q22 region for the involved gene(s) in HCC. High-resolution mapping analysis highlighted 7 candidates, namely PFTAIRE protein kinase 1 (PFTK1), ODAG, CDK6, CAS1, PEX1, SLC25A, and PEG10, within the region. H epatocellular carcinoma (HCC) is the fifth most common cancer worldwide 1 and the third most common cause of cancer-related mortality. One of the reasons for this high mortality is that the tumour usually presents at a stage when curative surgery is no longer feasible because of intrahepatic or extrahepatic metastases. Although the 5-year survival of HCC patients who have undergone hepatectomy has improved in recent years, postoperative intrahepatic recurrence can still be as high as 43% by 2 years after resection, 2 presumably because of preexisting micro-metastases. 3 These observations underscore the urgent need to understand the molecular characteristics and related biological mechanisms in tumor cell dissemination.Despite extensive studies, the underlying genomic alterations in HCC remain poorly understood, 4-6 and few tumor suppressors or proto-oncogenes have been related to metastasis and recurrences. Utilizing genetic information derived from a cohort of 100 HCC tumors analyzed by chromosome-based comparative genomic hybridization (CGH), our group has previously shown several regional chromosome gains, especially over-representations

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“…This may reflect the stronger and more sustained nature of PKC activation by PMA than ANG II. The involvement of PKC has been shown in the activation of PAK in HepG2 cells (19). Schmitz et al (32) also previously reported PKC-dependent activation of PAK by ANG II in VSMCs.…”

Section: Discussionmentioning

confidence: 86%

Angiotensin II-induced activation of p21-activated kinase 1 requires Ca²⁺ and protein kinase Cδ in vascular smooth muscle cells

Woolfolk¹,

Eguchi²,

Ohtsu³

et al. 2005

American Journal of Physiology-Cell Physiology

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ANG II promotes remodeling of vascular smooth muscle cells (VSMCs) in cardiovascular diseases. It has been shown to activate p21-activated kinase (PAK)1, a critical component of signaling pathways implicated in growth and migration. However, the detailed signaling mechanism by which ANG II induces PAK1 activation in VSMCs remains unclear. Therefore, we have examined the mechanism required for activation of PAK1 by ANG II in VSMCs. ANG II, through activation of the ANG II type 1 receptor, rapidly promotes phosphorylation of PAK1 in VSMCs via a pathway independent of transactivation of the epidermal growth factor receptor. Using selective agonists and inhibitors, we demonstrated that mobilization of intracellular Ca(2+) and PKCdelta activation are required for ANG II-induced PAK1 phosphorylation. Rottlerin, a PKCdelta inhibitor, significantly blocked ANG II-induced PAK1 phosphorylation. Further support for this notion was provided through infection of VSMCs with adenovirus encoding a dominant-negative (dn)PKCdelta, which also markedly reduced phosphorylation of PAK1 by ANG II. In this pathway, Ca(2+) acts upstream of PKCdelta because a Ca(2+) ionophore rapidly induced PKCdelta phosphorylation at Tyr311 and Ca(2+)-dependent PAK1 phosphorylation was blocked by rottlerin. In addition, dnPYK-2, dnRac, and antioxidants inhibited ANG II-induced PAK1 phosphorylation, suggesting that PYK-2, Rac, and reactive oxygen species are involved in the upstream signaling. Finally, dnPAK1 markedly inhibited ANG II-induced protein synthesis in VSMCs. These data provide a novel signaling pathway by which ANG II may contribute to vascular remodeling.

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Phorbol ester-induced migration of HepG2 cells is accompanied by intensive stress fibre formation, enhanced integrin expression and transient down-regulation of p21-activated kinase 1

Cited by 18 publications

References 41 publications

Regulation of de novo phosphatidylinositol synthesis

Regulation of de novo phosphatidylinositol synthesis

Identification ofPFTAIREprotein kinase 1, a novel cell division cycle-2 related gene, in the motile phenotype of hepatocellular carcinoma cells

Angiotensin II-induced activation of p21-activated kinase 1 requires Ca²⁺ and protein kinase Cδ in vascular smooth muscle cells

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Phorbol ester-induced migration of HepG2 cells is accompanied by intensive stress fibre formation, enhanced integrin expression and transient down-regulation of p21-activated kinase 1

Cited by 18 publications

References 41 publications

Regulation of de novo phosphatidylinositol synthesis

Regulation of de novo phosphatidylinositol synthesis

Identification ofPFTAIREprotein kinase 1, a novel cell division cycle-2 related gene, in the motile phenotype of hepatocellular carcinoma cells

Angiotensin II-induced activation of p21-activated kinase 1 requires Ca2+ and protein kinase Cδ in vascular smooth muscle cells

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Angiotensin II-induced activation of p21-activated kinase 1 requires Ca²⁺ and protein kinase Cδ in vascular smooth muscle cells