Isothiocyanate E-4IB induces MAPK activation, delayed cell cycle transition and apoptosis.
BACKGROUND
Epidemiologic studies point towards a significant correlation between the dietary intake of isothiocyanate-containing foods and the reduced risk for cancer.


RESULTS
In the current investigation, we examined the consequence of activating of signalling pathways during the release the cells from the block at G(1)/S boundary by synthetic isothiocyanate E-4IB. Using synchronized leukaemic HL60 cells, we show that activation of mitogen-activated protein kinases ERK1/2, c-Jun N-terminal kinase and p38 signalling pathways by E-4IB are coupled with delayed transition through the cell cycle and rapid cell cycle arrest resulted in diminished mitochondrial membrane potential culminating in apoptosis. These events were accompanied by histone deacetylase inhibition, increase of double strand DNA breaks detected by histone H2AX phosphorylation and up-regulation of cell cycle regulatory protein p21 and phosphorylation of CDC25C phosphatase.


CONCLUSIONS
These findings suggest that the activation of mitogen-activated protein kinases signalling pathways, followed by the induction cell cycle arrest and apoptosis, might be responsible for anticancer activities of E-4IB.
Bodo
J
J
Laboratory of Tumour Immunology, Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Duraj
J
J
Jakubikova
J
J
Sedlak
J
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D018922:HL-60 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D016196:S Phase / Q000187:drug effects*; D020687:cdc25 Phosphatases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D002087:Butyrates; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D017879:Isothiocyanates; C082832:ethyl 4-isothiocyanatobutanoate; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D006655:Histone Deacetylases