okadaic-acid and Neoplasms

The okadaic acid class of tumor promoters, which are inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A), induced tumor promotion in mouse skin, rat glandular stomach, and rat liver. Endogenous protein inhibitors of PP2A, SET and CIP2A, were up-regulated in various human cancers, so it is vital to review the essential mechanisms of tumor promotion by the okadaic acid class compounds, together with cancer progression by SET and CIP2A in humans.. The first part of this review introduces the okadaic acid class compounds and the mechanism of tumor promotion: (1) inhibition of PP1 and PP2A activities of the okadaic acid class compounds; (2) some topics of tumor promotion; (3) TNF-α gene expression as a central mediator in tumor promotion; (4) exposure to the okadaic acid class of tumor promoters in relation to human cancer. The second part emphasizes the overexpression of SET and CIP2A in cancer progression, and the anticancer activity of SET antagonists as follows: (5) isolation and characterization of SET; (6) isolation and characterization of CIP2A; (7) progression of leukemia with SET; (8) progression of breast cancer with SET and CIP2A; (9) progression of lung cancer with SET; (10) anti-carcinogenic effects of SET antagonists OP449 and FTY720; and also (11) TNF-α-inducing protein of Helicobacter pylori, which is a clinical example of the okadaic acid pathway.. The overexpression of endogenous protein inhibitors of PP2A, SET and CIP2A, is tightly linked to the progression of various human cancers, as well as Alzheimer's disease.

Topics: Animals; Autoantigens; Biomarkers, Tumor; Cell Transformation, Neoplastic; Disease Progression; DNA-Binding Proteins; Environmental Exposure; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Histone Chaperones; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Molecular Targeted Therapy; Neoplasms; Okadaic Acid; Protein Phosphatase 2; Signal Transduction; Transcription Factors; Tumor Necrosis Factor-alpha

Microcystin-LR and nodularin, along with okadaic acid, are potent inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A). The mechanisms of action of microcystin-LR and nodularin in the liver and that of okadaic acid, a potent tumor promoter on mouse skin, have attracted the attention of the scientists. This paper reviews several topics: new inhibitors of PP1 and PP2A with new chemical structures, structure-function relationships for both receptor binding and inhibition of protein phosphatases, the crystal structure of PP1 or PP2A-toxin complex, induction of gene expression and apoptosis. These subjects were studied by using in vitro and in vivo experimental systems. Two-stage carcinogenesis experiments with microcystin-LR and nodularin for the first time demonstrated that microcystin-LR is a new tumor promoter in rat liver initiated with diethylnitrosamine (DEN), and that nodularin is a potent tumor promoter associated with weak initiating activity in rat liver initiated with DEN. A working group of WHO (IARC) concluded that microcystin-LR is "possibly carcinogenic to humans" and that nodularin is "not classifiable as to carcinogenicity". Our studies revealed that chemical tumor promoters are inducers of TNF-α in the cells of target tissues and that TNF-α is an endogenous tumor promoter. This advance in carcinogenesis made it possible to look for the link between chemical tumor promoters and endogenous tumor promoters, such as TNF-α and IL-1. The carcinogenic features of TNF-α are described in this review, and the TNF-α inducing protein (Tipα) of Helicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development.

Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; Humans; Marine Toxins; Microcystins; Neoplasms; Okadaic Acid; Peptides, Cyclic; Protein Tyrosine Phosphatases; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Okadaic acid is functionally a potent tumor promoter working through inhibition of protein phosphatases 1 and 2A (PP1 and PP2A), resulting in sustained phosphorylation of proteins in cells. The mechanism of tumor promotion with okadaic acid is thus completely different from that of the classic tumor promoter phorbol ester. Other potent inhibitors of PP1 and PP2A - such as dinophysistoxin-1, calyculins A-H, microcystin-LR and its derivatives, and nodularin - were isolated from marine organisms, and their structural features including the crystal structure of the PP1-inhibitor complex, tumor promoting activities, and biochemical and biological effects, are here reviewed. The compounds induced tumor promoting activity in three different organs, including mouse skin, rat glandular stomach and rat liver, initiated with three different carcinogens. The results indicate that inhibition of PP1 and PP2A is a general mechanism of tumor promotion applicable to various organs. This study supports the concept of endogenous tumor promoters in human cancer development.

Topics: Animals; Carcinogens; Disease Progression; Enzyme Inhibitors; Humans; Marine Toxins; Mice; Models, Molecular; Neoplasms; Neoplasms, Experimental; Okadaic Acid; Oxazoles; Protein Phosphatase 1; Protein Phosphatase 2; Rats; Skin Neoplasms; Stomach Neoplasms; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Tumor promotion is a critical point in multistage carcinogenesis in humans. We have identified a common biochemical and molecular tumor promotion mechanism, the okadaic acid pathway, applicable in various organs. Tumor promotion by the okadaic acid class of compounds is mediated through inhibition of protein phosphatases 1 and 2A, resulting in an increase of protein phosphorylation and a subsequent expression of cell proliferation genes. Recently, we demonstrated that okadaic acid induced the release of mouse tumor necrosis factor-alpha (mTNF-alpha) from BALB/3T3 cells. The first part of this review discusses the link between the okadaic acid pathway and TNF-alpha as endogenous tumor promoters in vivo. Inhibitors of tumor promotion are varied. For the purpose of cancer chemoprevention in humans, the inhibitors sarcophytol A, canventol, and (-)-epigallocatechin gallate (EGCG) were studied and the results are presented. The inhibitory mechanisms also were varied: sarcophytol A inhibited H2O2 formation by TPA-activated human polymorphonuclear leukocytes; canventol inhibited protein isoprenylation in the cells; and EGCG, which is a main constituent of Japanese green tea, is an antioxidant. These inhibitors are promising cancer chemopreventive agents. Study of the essential tumor promotion mechanisms will facilitate the development of cancer chemopreventive agents.

Topics: Anticarcinogenic Agents; Catechin; Cyclohexanols; Diterpenes; Ethers, Cyclic; Humans; Neoplasms; Okadaic Acid; Tumor Necrosis Factor-alpha

Topics: Animals; Antifungal Agents; Carcinogens; Ethers, Cyclic; Humans; Microcystins; Neoplasms; Okadaic Acid; Peptides, Cyclic; Phosphoprotein Phosphatases; Pyrans; Spiro Compounds; Structure-Activity Relationship

Resveratrol, a natural polyphenol compound, has been shown to possess anticancer activity. However, how resveratrol inhibits cancer cell adhesion has not been fully elucidated. Here, we show that resveratrol suppressed the basal or type I insulin-like growth factor (IGF)-1-stimulated adhesion of cancer cells (Rh1, Rh30, HT29, and HeLa cells) by inhibiting the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway. Inhibition of Erk1/2 with U0126, knockdown of Erk1/2, or overexpression of dominant-negative mitogen-activated protein kinase kinase 1 (MKK1) strengthened resveratrol's inhibition of the basal or IGF-1-stimulated of Erk1/2 phosphorylation and cell adhesion, whereas ectopic expression of constitutively active MKK1 attenuated the inhibitory effects of resveratrol. Further research revealed that both protein phosphatase 2A (PP2A) and phosphatase and tensin homolog (PTEN)-Akt were implicated in resveratrol-inactivated Erk1/2-dependent cell adhesion. Inhibition of PP2A with okadaic acid or overexpression of dominant-negative PP2A rendered resistance to resveratrol's suppression of the basal or IGF-1-stimulated phospho-Erk1/2 and cell adhesion, whereas expression of wild-type PP2A enhanced resveratrol's inhibitory effects. Overexpression of wild-type PTEN or dominant-negative Akt or inhibition of Akt with Akt inhibitor X strengthened resveratrol's inhibition of the basal or IGF-1-stimulated Erk1/2 phosphorylation and cell adhesion. Furthermore, inhibition of mechanistic/mammalian target of rapamycin (mTOR) with rapamycin or silencing mTOR enhanced resveratrol's inhibitory effects on the basal and IGF-1-induced inhibition of PP2A-PTEN, activation of Akt-Erk1/2, and cell adhesion. The results indicate that resveratrol inhibits Erk1/2-mediated adhesion of cancer cells via activating PP2A-PTEN signaling network. Our data highlight that resveratrol has a great potential in the prevention of cancer cell adhesion.

Topics: Butadienes; Cell Adhesion; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; HeLa Cells; HT29 Cells; Humans; Insulin-Like Growth Factor I; MAP Kinase Kinase 1; MAP Kinase Signaling System; Neoplasms; Nitriles; Okadaic Acid; Oncogene Protein v-akt; Protein Phosphatase 2; PTEN Phosphohydrolase; Resveratrol; Signal Transduction; TOR Serine-Threonine Kinases

Telomerase plays fundamental roles in bypassing cellular aging and promoting cancer progression by maintaining telomere homeostasis and telomere-independent activities. However, the molecular mechanisms by which telomerase provokes aging and cancer are far from being fully understood. In a search for proteins interacting with human telomerase reverse transcriptase hTERT by the yeast two-hybrid screen using hTERT T-motif as bait, we identified PP2A scaffolding subunit PR65 alpha isoform as an hTERT interacting partner. We showed that both PP2A catalytic subunit PP2AC and scaffolding subunit PR65 interacted with hTERT in vivo and in vitro and inhibited telomerase activity. In addition, we found that PP2A prevented the interaction of hTERT with 14-3-3θ signaling protein, an hTERT binding partner that is required for nuclear localization of hTERT. Activation of PP2A by overexpression of PP2AC or PR65 led to cytoplasmic accumulation of hTERT, which was reversed by treatment with PP2A inhibitor okadaic acid. Together, these observations suggest that PP2A regulates hTERT subcellular localization, in addition to its inhibitory effects on telomerase activity.

Topics: 14-3-3 Proteins; Apoptosis; Biomarkers, Tumor; Cell Nucleus; Cell Transformation, Neoplastic; Cellular Senescence; Exonucleases; Exoribonucleases; Gene Expression; HeLa Cells; Humans; Neoplasms; Okadaic Acid; Protein Binding; Protein Phosphatase 2; Telomerase; Telomere

Viruses have evolved an assortment of mechanisms for regulating the Akt signaling pathway to establish a cellular environment more favorable for viral replication. Myxoma virus (MYXV) is a rabbit-specific poxvirus that encodes many immunomodulatory factors, including an ankyrin repeat-containing host range protein termed M-T5 that functions to regulate tropism of MYXV for rabbit lymphocytes and certain human cancer cells. MYXV permissiveness in these human cancer cells is dependent upon the direct interaction between M-T5 and Akt, which has been shown to induce the kinase activity of Akt. In this study, an array of compounds that selectively manipulate Akt signaling was screened and we show that only a subset of Akt inhibitors significantly decreased the ability of MYXV to replicate in previously permissive human cancer cells. Furthermore, reduced viral replication efficiency was correlated with lower levels of phosphorylated Akt. In contrast, the PP2A-specific phosphatase inhibitor okadaic acid promoted increased Akt kinase activation and rescued MYXV replication in human cancer cells that did not previously support viral replication. Finally, phosphorylation of Akt at residue Thr308 was shown to dictate the physical interaction between Akt and M-T5, which then leads to phosphorylation of Ser473 and permits productive MYXV replication in these human cancer cells. The results of this study further characterize the mechanism by which M-T5 exploits the Akt signaling cascade and affirms this interaction as a major tropism determinant that regulates the replication efficiency of MYXV in human cancer cells.

Topics: Cell Line, Tumor; Fingolimod Hydrochloride; Humans; Intracellular Signaling Peptides and Proteins; Myxoma virus; Neoplasms; Okadaic Acid; Phosphoric Monoester Hydrolases; Phosphorylation; Propylene Glycols; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; Sphingosine; TOR Serine-Threonine Kinases; Viral Proteins; Viral Tropism; Virus Replication

Previous studies indicated that cells whose chromatin is naturally compacted at the time of radiation are hypersensitive to radiation-induced killing, primarily by single-hit inactivation. Some chemicals that are known to promote chromatin compaction in interphase cells are here investigated for their radiosensitizing potential.. Okadaic acid (OA), a protein phosphatase inhibitor, fostriecin (FC), a topoisomerase II inhibitor and trichostatin A (TSA), a histone deacetylase inhibitor, were reported to promote chromatin compaction in mammalian cells. Asynchronous populations of HT-29 (human colon carcinoma) cells were exposed to various concentrations of OA, FC and TSA for various times before irradiation with various doses of Cs-137 gamma-rays and toxicity and radiosensitization were measured. Induced chromatin compaction was visualized by electron microscopy (EM). Histone 1 (H1) and histone 3 (H3) phosphorylation was measured by Western blotting, whole-cell fluorescence microscopy and confocal microscopy.. OA and FC produced significant radiosensitization at 2 Gy after short (2 h) exposures. These chemical treatments also produced increased phosphorylation of H3 and increased chromatin compaction as measured by EM. A 2-h exposure of cells to TSA had no effect on cell radiosensitivity, histone phosphorylation or chromatin condensation. However, a 16-h exposure to TSA produced significant radiosensitization, histone phosphorylation and chromatin condensation, presumably by secondary mechanisms.. These data are consistent with the hypothesis that compacted chromatin is a hypersensitive target for radiation killing. Furthermore, the modulation of chromatin conformation by drugs selectively in tumour cells might radiosensitize tumours whose cells are intrinsically radioresistant.

Topics: Alkenes; Cell Survival; Chromatin; Histones; HT29 Cells; Humans; Hydroxamic Acids; Immunohistochemistry; Neoplasms; Okadaic Acid; Polyenes; Pyrones; Radiation Tolerance

Vascular endothelial growth factor (VEGF) is a specific mitogen for vascular endothelial cells and has been implicated in tumor angiogenesis. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, is a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoter in two-stage carcinogenesis experiments in mouse skin. To elucidate the role of VEGF in the angiogenesis of these experimental tumors, the effect of okadaic acid on VEGF gene expression was examined. In NIH 3T3, Rat1, HeLa, and A431 cells, VEGF mRNA was upregulated by 5- to 10-fold after incubation with okadaic acid. Furthermore, the amount of VEGF protein in the culture medium was significantly increased after stimulation with okadaic acid. Interestingly, okadaic acid-induced upregulation of VEGF mRNA was not suppressed by protein kinase C (PKC) inhibitor or by tumor necrosis factor alpha blocking antibody, although TPA-induced VEGF upregulation was strongly suppressed by PKC inhibitor. Our results indicate that okadaic acid is a new and potent inducer of VEGF, suggesting the involvement of VEGF as an angiogenic factor during multistep carcinogenesis in vivo.

Topics: 3T3 Cells; Animals; Antifungal Agents; Cell Line; Culture Media; Endothelial Growth Factors; Enzyme Inhibitors; HeLa Cells; Humans; Lymphokines; Mice; Neoplasms; Neovascularization, Pathologic; Neutralization Tests; Okadaic Acid; Phosphoprotein Phosphatases; Protein Kinase C; Pyrans; Rats; RNA, Messenger; Spiro Compounds; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Amines; Animals; Anticarcinogenic Agents; Awards and Prizes; Carcinogens, Environmental; Dietary Proteins; Environmental Health; Flavonoids; Food; Heterocyclic Compounds; History, 20th Century; Hot Temperature; Humans; Japan; Medical Oncology; Mice; Mice, Transgenic; Mutagenesis; Neoplasms; Okadaic Acid; Rats

Many factors are involved in the development of drug resistance for anticancer drugs. The drugs should pharmacokinetically attain the appropriate concentration. They should be metabolized to the active forms. Tumor cells should have sensitivity to them. Several molecular and biochemical mechanisms that may explain cellular drug resistance have been identified. The contribution of protein phosphorylation and dephosphorylation for drug resistance is demonstrated in phorbol ester and okadaic-acid-resistant cells. The modulation of drug resistance by substances that affect the signal transduction pathway is an important issue in the development of an effective method for overcoming drug resistance.

Topics: Antineoplastic Agents; Carcinogens; Cell Line; Cisplatin; Doxorubicin; Drug Resistance; Drug Resistance, Multiple; Enzyme Inhibitors; Ethers, Cyclic; Humans; Neoplasm Proteins; Neoplasms; Okadaic Acid; Phorbol Esters; Phosphorylation; Protein-Tyrosine Kinases; Signal Transduction