Direct inhibition of ERK1/2 phosphorylation as a possible mechanism for the antiproliferative action of 3,4-diOH-PCB3 in the MCF-7 cell line.
Our previously published data showed that 260h of exposure to 3,4-diOH-PCB3 decreased proliferation in the MCF-7 cell line. In the present study, we sought to determine whether this is due to action on the SHBG/cAMP/PKA system, activation of which can inhibit cell proliferation, or to direct inhibition of ERK1/2 phosphorylation. MCF-7 human breast cancer cells were treated for 72h with 4-monochlorobiphenyl (PCB3), 4'-hydroxy-4-monochlorobiphenyl (4-OH-PCB3) or 3'4'-dihydroxy-4-monochlorobiphenyl (3,4-diOH-PCB3) (300nM). After the completion of the treatment, cell proliferation was measured with a BrdU incorporation assay. SHBG, cAMP, PKA and ERK1/2 levels in the cells were determined via ELISA. PCB3 and 4-OH-PCB3 had no effect on extra- or intracellular SHBG levels, while a stimulation of SHBG intra- but not extracellular levels was noted in cells exposed to 3,4-diOH-PCB3. Both, pre- and co-incubation with SHBG decreased the proliferation of 3,4-diOH-PCB3-treated cells. Neither PCB3 nor its metabolite had an effect on the cAMP/PKA pathway. A decrease of both ERK1/2 forms was noted under the influence of 3,4-diOH-PCB3. In conclusion, the data presented clearly showed that the antiproliferative action of 3,4-diOH-PCB3 is not mediated by activation of the SHBG/AMP/PKA pathway, but many other plasma membrane receptors seem to be involved in the non-genomic action of 3,4-diOH-PCB3, and instead is due to direct inhibition of the ERK1/2 system.
Ptak
Anna
A
Department of Physiology and Toxicology of Reproduction, Institute of Zoology, Jagiellonian University, 30-060 Kraków, Ingardena 6, Poland.
Gut
Patrycja
P
Błachuta
Małgorzata
M
Rak
Agnieszka
A
Gregoraszczuk
Ewa Ł
EŁ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D015290:Second Messenger Systems / Q000187:drug effects; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C543847:3',4'-dihydroxy-4-monochlorobiphenyl; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D012738:Sex Hormone-Binding Globulin; D011078:Polychlorinated Biphenyls; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3