Different mechanisms of action of 2, 2’, 4, 4’‐tetrabromodiphenyl ether (BDE‐47) and its metabolites (5‐OH‐BDE‐47 and 6‐OH‐BDE‐47) on cell proliferation in OVCAR‐3 ovarian cancer cells and MCF‐7 breast cancer cells

Abstract

Data concerning the possible action of polybrominated diphenyl ethers (PBDEs) in hormone-dependent cancer are scarce. Some data showed that PBDEs may directly affect breast cancer cells formation and only one research showed increased proliferation of the OVCAR-3 cells, but the results are ambiguous and the mechanisms are not clear. There is growing evidence that not only parent compounds but also its metabolites may be involved in cancer development. The present study was, therefore, designed to determine the effect of BDE-47 and its metabolites (2.5 to 50 ng ml ) on proliferation (BrdU), cell-cycle genes (real-time PCR) and protein expression (Western blot), protein expression of oestrogen receptors (α β), extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase Cα (PKCα) in OVCAR-3 ovarian and MCF-7 breast cancer cells. In OVCAR-3 cells, the parent compound stimulated cell proliferation by activating CDK1, CDK7, E2F1 and E2F2. Independent of time of exposure, BDE-47 had no effect on ERα and ERβ protein expression and ERK1/2 and PKCα phosphorylation. Metabolites had no effect on cell proliferation but increased both ERs protein expression and ERK1/2 and PKCα phosphorylation. In MCF-7 cells, the parent compound displayed no effect on cell proliferation but decreased ERα and increased ERβ protein expression with concomitant induction of PKCα phosphorylation. Both metabolites increased MCF-7 cell proliferation, ERK1/2 and PKCα phosphorylation and decreased ERα and ERβ protein expression.We suggest that studies concerning PBDEs with fewer bromine atoms should be continued to understand environmental links to different hormone-dependent cancers. Copyright © 2016 John Wiley & Sons, Ltd.

Differences in the mechanisms of action of BDE‐47 and its metabolites on OVCAR‐3 and MCF‐7 cell apoptosis

“…The results of our previous study (Karpeta et al, 2016), showed that BDE-47 increased OVCAR-3 cell proliferation mainly via the activation of cell cycle genes and protein expression and hydroxylated metabolites of BDE-47 stimulated MCF-7 proliferation through genomic action (an increase in cell cycle genes and protein expression, and the downregulation of estrogen receptors) and non-genomic action (the activation of ERK1/2 and PKCα phosphorylation). Data from aforementioned study showed cell-specific action of the parent compound, while a similar effect of metabolites on apoptosis in both OVCAR-3 and MCF-7 cells.…”

“…Hydroxylated metabolites of PBDE were found to be potent agonists of estrogen receptors (Kojima et al, ) and thus might affect apoptosis in MCF‐7 cells in a similar way to estradiol. Our previous studies showed that hydroxylated metabolites (5‐OH‐BDE‐47 and 6‐OH‐BDE‐47) increased the estrogen receptor protein expression in OVCAR‐3 and MCF‐7 cells (Karpeta et al, ). Increased expression of estrogen receptors by 5‐OH‐BDE‐47 and 6‐OH‐BDE‐47 increases the number of binding sites for both endogenous and exogenous estrogens suggesting potential carcinogenic action of hydroxylated PBDE metabolites.…”

“…In conclusion, presented results clearly showed that hydroxylated metabolites of BDE-47 have stronger inhibitory effects on apoptosis in both ovarian and breast tumor cells than the parent compound (BDE-47). Moreover, our previous study showed that hydroxylated metabolites of BDE-47 increased estradiol secretion by ovarian follicles (Karpeta et al, 2013) and suggest that 5-OH-BDE-47 and 6-OH-BDE-47 may bind with estrogen receptors in place of estradiol, thus triggering estrogenic action in mammary tissue (Karpeta et al, 2016). Taking into consideration the data showing that in MCF-7 cell expression of several pro-apoptotic proteins are markedly increased with estradiol treatment (Lewis et al, 2005) and data showing that estradiol inhibit apoptosis in ovarian tumorigenesis (Choi et al, 2001) we may confirm that metabolites are much more potent than the parent compound.…”

“…Therefore, as one of the mechanisms of inhibitory effect of hydroxylated metabolites on apoptosis, we suggest activation of the ERK1/2 and PKCα pathway. In previous research, we proposed activation of ERK1/2 and PKCα in ovarian and breast cancer cells as a mechanism of stimulatory action of 5‐OH‐BDE‐47 and 6‐OH‐BDE‐47 on cell proliferation (Karpeta et al, ). The results of Li et al (), who showed that BDE‐209 antagonized PD98059‐ and Gӧ 6976‐induced apoptosis in OVCAR‐3 and MCF‐7 cells, agree with our results.…”

“…The results of our previously published data showed that BDE‐47 increased OVCAR‐3 cell proliferation, whereas hydroxylated metabolites of BDE‐47 stimulated MCF‐7 proliferation (Karpeta et al, ). To confirm further the published results suggesting involvement of PBDEs in tumorigenesis, in this study we investigated the effect of BDE‐47 and its hydroxylated metabolites 5‐OH‐BDE‐47 and 6‐OH‐BDE‐47 on expression of apoptosis regulatory genes and proteins both in the extrinsic and intrinsic pathway and on caspase‐8 and ‐9 activity in ovarian (OVCAR‐3) and breast (MCF‐7) cancer cell lines.…”