Degradation and Dephosphorylation of Focal Adhesion Kinase During Okadaic Acid-Induced Apoptosis in Human Neuroblastoma Cells

Kim, Bhumsoo; Golen, Cynthia M. van; Feldman, Eva L.

doi:10.1016/s1476-5586(03)80043-x

Cited by 28 publications

(29 citation statements)

References 79 publications

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“…redistribution of the F-actin network concomitant with cell detachment, as described by Kim et al (2003) in SH-EP human neuroblastoma cells treated with OA. However, the cells did not show the characteristic F-actin punctuated distribution, consequence of the treatment with other natural compounds that disorganize the actin cytoskeleton, for instance, pectenotoxins.…”

Section: Sensitivity Of Hepatocytes To Methyl Okadaate B Espiña Et Almentioning

confidence: 81%

The methyl ester of okadaic acid is more potent than okadaic acid in disrupting the actin cytoskeleton and metabolism of primary cultured hepatocytes

Espiña

Louzao

Cagide

et al. 2010

British J Pharmacology

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The methyl ester of okadaic acid is more potent than okadaic acid in disrupting the actin cytoskeleton and metabolism of primary cultured hepatocytesb ph_512 337.. 344 Begoña Espiña Japan Food Research Laboratories, Tama, Tokyo 206-0025, JapanBackground and purpose: Okadaic acid (OA) and microcystins (MCs) are structurally different toxins with the same mechanism of action, inhibition of serine/threonine protein phosphatases (PPs). Methyl okadaate (MeOk), a methyl ester derivative of OA, was considered almost inactive due to its weak inhibition of PP1 and PP2A. Here, we have investigated the activity and potency of MeOk in hepatic cells in comparison with that of OA and MCs. Experimental approach: We tested the effects of MeOK, OA and microcystin-leucine and arginine (MC-LR) on the metabolic rate, the actin cytoskeleton and glucose uptake in a rat hepatocyte cell line (Clone 9) and in primary cultured rat hepatocytes. PP2A was assayed to compare OA and MeOk activity. Key results: MeOk disrupted the actin cytoskeleton and depressed the metabolic rate of both types of rat hepatocytes, being six-fold less potent than OA in Clone 9 cells but nearly six-fold more potent in primary cultured hepatocytes. However, unlike OA, MeOk did not change glucose uptake in these cells, suggesting a weak inhibition of PP2A, as confirmed in direct assays of PP2A activity. Conclusions and implications:Although MeOk was originally described as a weakly bioactive molecule, it clearly depressed the metabolic rate and disrupted the cytoskeleton in primary and immortalized rat hepatocytes. Furthermore, MeOk affected primary hepatocytes at much lower concentrations than those affecting immortalized cells. These effects were unrelated to PP2A inhibition. Our results suggest the risk to public health from MeOk in foodstuffs should be re-evaluated.British Journal of Pharmacology (2010) 159, 337-344; doi:10.1111/j.1476-5381.2009 published online 15 December 2009 Keywords: actin cytoskeleton; glucose uptake kinetics; metabolic rate; methyl okadaate; microcystin; okadaic acid; phycotoxins; protein phosphatase and rat hepatocytes Abbreviations: DSP, diarrheic shellfish poisoning; MC-LR, microcystin-leucine and arginine; MeOk, methyl okadaate; OA, okadaic acid; PP1, protein phosphatase-1; PP2A, protein phosphatase-2A IntroductionMany natural toxins such as okadaic acid (OA) potently inhibit the catalytic activity of serine/threonine protein phosphatases (PPs), of which PP1 and PP2A are the most abundant in cells. Both PPs have a wide spectrum of activity being able to dephosphorylate a large number of substrates in vitro (Fernandez et al., 2002). The list of PPs inhibitors includes a structurally diverse group of compounds: polyether fatty acid substances similar to okadaic acid (OA), cyclic peptides like microcystins (MCs) and nodularins, terpenoids such as cantharidin and thyrsiferyl 23-acetate and polyketides, such as tautomycin and calyculin A (Fernandez et al., 2002). OA is the best representative of the diarrheic shellfish poisoning ...

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Section: Sensitivity Of Hepatocytes To Methyl Okadaate B Espiña Et Almentioning

confidence: 81%

The methyl ester of okadaic acid is more potent than okadaic acid in disrupting the actin cytoskeleton and metabolism of primary cultured hepatocytes

Espiña

Louzao

Cagide

et al. 2010

British J Pharmacology

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“…Kim et al (18) reported that okadaic acid induces cell detachment, which is accompanied by FAK dephosphorylation. Zouq et al (7) reported that fibroblasts and epithelial cells exhibit rapid dephosphorylation of FAK in response to detachment from the ECM.…”

Section: Discussionmentioning

confidence: 99%

Cbl-b promotes cell detachment via ubiquitination of focal adhesion kinase

Fan

et al. 2016

Oncology Letters

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Abstract. Cancer cell detachment from the primary tumor site represents the first stage of metastasis. Previous studies have identified that cell detachment is triggered by cytoskeletal disruption, which may induce a wide variety of cellular changes. Focal adhesion kinase (FAK) exhibits crucial cellular functions, including regulation of the cytoskeleton. These observations have provided exciting insights into the effect of FAK in cell detachment; however, the involvement of FAK in cell detachment remains controversial. The aim of the present study was to evaluate the effect of FAK and its function in the process of cell detachment. The results revealed that FAK expression was downregulated following trypsin treatment in human gastric, lung, colon and breast cancer cell lines, as well as a human gastric epithelial cell line. Knockdown of FAK enhanced cell detachment in gastric cancer MGC803 cells, indicating that FAK inhibits cell detachment. Further investigation revealed that trypsin induced monoubiquitination of FAK. In addition, the lysosome inhibitor, NH 4 Cl, decreased trypsin-induced degradation of FAK. Casitas B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, was involved in this process, which interacted with FAK, as demonstrated by co-precipitation experiments, and promoted trypsin-induced ubiquitin-lysosome degradation of FAK. These results indicate that Cbl-b promotes cell detachment via ubiquitination of FAK. These findings provide novel insights regarding the effect of FAK and Cbl-b in the process of cancer cell detachment.

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“…Agents such as OA, cycloheximide, or Taxol attenuate growth of diverse cell types in part by causing apoptosis (11,12,14,15). To investigate mechanisms of HBC growth suppression by these agents, HBC cells were exposed to 120 nmol/L OA, 0.7 mmol/L cycloheximide, or 30 Amol/L Taxol for varying periods of time, followed by determination of cell viability using MTT assay.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of PP2A by agents such as okadaic acid (OA 2 ; a specific inhibitor of PP1 and PP2A), on the other hand, interferes with dephosphorylation of c-Myc, resulting in its elevated expression (9). Although global inhibition of PP2A often results in enhanced transformation of cells (10), exposure to OA has also been shown to inhibit cell growth in part by stimulating apoptosis (11,12). However, the precise nature of the pathways targeted by OA and potential role of c-Myc in OA-dependent cell growth suppression signaling remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Cell Growth Inhibition by Okadaic Acid Involves Gut-Enriched Kruppel-like Factor–Mediated Enhanced Expression of c-Myc

et al. 2007

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Human breast cancer (HBC) cell growth suppression by okadaic acid (OA) was previously found to involve elevated expression of oncogenes c-myc and c-fos and apoptosis. Since, c-Myc influences diverse pathways of cell growth, we hypothesized that elevated levels of c-Myc are involved in HBC growth suppression. Here, we investigated whether induction of c-Myc by OA or protein synthesis inhibitor cycloheximide contributed to HBC growth inhibition and the mechanisms involved. OA, cycloheximide, or the chemotherapeutic drug Taxol suppressed HBC cell growth. However, OA or cycloheximide treatments over 6 or 10 h, respectively, induced c-Myc expression. Depletion of c-Myc, on the other hand, resulted in enhanced HBC cell viabilities when exposed to OA or cycloheximide, but not by Taxol. OA induced c-myc transcription by targeting an 80-bp region from positions À11 to +70, relative to the P1 transcription start of mouse c-myc promoter. Gel mobility shift assays revealed binding of HBC cell nuclear proteins to the OA-responsive c-myc promoter fragment, whereas binding of one complex was elevated in the case of the OA-treated or cycloheximide-treated HBC cell nuclear extracts. Database search revealed presence of a consensus sequence for zinc finger protein gut-enriched Kruppel-like factor (GKLF) in OA-responsive region of the c-myc promoter. Mutation of GKLF consensus sequences abrogated OA responsiveness of the c-myc promoter, and OA treatments caused enhanced expression of GKLF in HBC cells. Thus, OA-dependent attenuation of HBC growth is accomplished, in part, by zinc finger transcription factor GKLFmediated enhanced transcription of c-myc. [Cancer Res 2007;67(21):10198-206]

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Degradation and Dephosphorylation of Focal Adhesion Kinase During Okadaic Acid-Induced Apoptosis in Human Neuroblastoma Cells

Cited by 28 publications

References 79 publications

The methyl ester of okadaic acid is more potent than okadaic acid in disrupting the actin cytoskeleton and metabolism of primary cultured hepatocytes

The methyl ester of okadaic acid is more potent than okadaic acid in disrupting the actin cytoskeleton and metabolism of primary cultured hepatocytes

Cbl-b promotes cell detachment via ubiquitination of focal adhesion kinase

Cell Growth Inhibition by Okadaic Acid Involves Gut-Enriched Kruppel-like Factor–Mediated Enhanced Expression of c-Myc

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