Insulin-like growth factor-1 and 17β-estradiol down-regulate prostate apoptosis response-4 expression in MCF-7 breast cancer cells

Casolari, Débora A.; Pereira, Michelly Cristiny; Garcia, Simone Aparecida de Bessa; Nagai, María Aparecida

doi:10.3892/ijmm.2011.691

Cited by 8 publications

(7 citation statements)

References 13 publications

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“…Indeed, as demonstrated by our analysis using bioinformatics datasets, estradiol negatively regulates Par-4 mRNA in MCF-7 breast cancer cell [49]. Another manuscript also stated the same negative effect on Par-4 in MCF-7 breast cancer cells treated with estradiol [78]. Likewise with the bioinformatics dataset, we also observed that the negative effect of estradiol on Par-4 could be canceled using a proteasome inhibitor, then leading to an increase of Par-4 in a way similar to what we observed in the case of cl-Par-4 throughout this manuscript in the context of proteasome inhibition.…”

Section: Discussionmentioning

confidence: 59%

Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells

et al. 2016

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We recently reported the caspase3-dependent cleavage of Par-4 resulting in the accumulation of a 25kDa cleaved-Par-4 (cl-Par-4) fragment and we investigated in the present study the mechanisms regulating this fragment using cl-Par-4-expressing stable clones derived from ovarian and endometrial cancer cell lines.Cl-Par-4 protein was weakly express in all stable clones despite constitutive expression. However, upon cisplatin treatment, cl-Par-4 levels increased up to 50-fold relative to baseline conditions. Treatment of stable clones with proteasome and translation inhibitors revealed that cisplatin exposure might in fact protect cl-Par-4 from proteasome-dependent degradation. PI3K and MAPK pathways were also implicated as evidenced by an increase of cl-Par-4 in the presence of PI3K inhibitors and a decrease using MAPK inhibitors. Finally using bioinformatics resources, we found diverse datasets showing similar results to those we observed with the proteasome and cl-Par-4 further supporting our data.These new findings add to the complex mechanisms regulating Par-4 expression and activity, and justify further studies addressing the biological significance of this phenomenon in gynaecological cancer cells.

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Section: Discussionmentioning

confidence: 59%

Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells

et al. 2016

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“…Indeed, this unique mechanism of selectivity has been demonstrated in various models and also seemed to be involved in chemoresistance (including Tamoxifen, taxane and platinum agents) and tumorigenesis mechanisms [172–176]. As previously described, gynecological tissues are known for being hormone-dependent and, interestingly, it has been demonstrated that estrogen can downregulate Par-4 and thus could be involved in chemoresistance-associated mechanisms [177, 178]. A study demonstrated that Par-4 increase the apoptotic response to paclitaxel treatment in ovarian cancer cells [179].…”

Section: Chemoresistance In Gynecological Cancersmentioning

confidence: 89%

Chemoresistance and targeted therapies in ovarian and endometrial cancers

2016

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Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers.

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“…Chan et al (27) reported that Par-4 mRNA and protein levels rapidly and progressively increase after trophic factor withdrawal in cultured rat hippocampal neurons and that Par-4 acts early in apoptosis (i.e., before mitochondrial dysfunction, caspase activation and nuclear changes). Previous results from our group also showed that withdrawal of estrogens and growth factors from the serum led to significantly increased Par-4 expression compared with the expression observed in MCF-7 cells maintained in media supplemented with 5% FBS (22). Furthermore, our group has demonstrated that Par-4 expression is negatively regulated by IGF-1 and the hormone 17β-estradiol (22).…”

Section: Discussionmentioning

confidence: 51%

“…Previous results from our group also showed that withdrawal of estrogens and growth factors from the serum led to significantly increased Par-4 expression compared with the expression observed in MCF-7 cells maintained in media supplemented with 5% FBS (22). Furthermore, our group has demonstrated that Par-4 expression is negatively regulated by IGF-1 and the hormone 17β-estradiol (22). These findings are in agreement with results from another study, in which cholangiocarcinoma cells cultured in the absence of serum exhibited Par-4 protein increased expression associated with a significant increase in BAX protein (21).…”

Section: Discussionmentioning

confidence: 51%

“…In cholangiocarcinoma cells, cell proliferation is associated with reduced Par-4 expression as cells selectively silenced for Par-4 demonstrated a significant increase in cell proliferation and reduced apoptosis (21). Recently, we have demonstrated that the mitogenic factors E2 and insulin-like growth factor-1 (IGF-1) lead to inhibition of Par-4 expression, suggesting that this downregulation contributes to breast cancer cell survival (22). To date, there is no report in the literature on the role of Par-4 in modulating breast cancer cell proliferation and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Prostate apoptosis response-4 is involved in the apoptosis response to docetaxel in MCF-7 breast cancer cells

Pereira

Garcia

Burikhanov

et al. 2013

International Journal of Oncology

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Experimental evidence indicates that prostate apoptosis response-4 (Par-4, also known as PAWR) is a key regulator of cancer cell survival and may be a target for cancer-selective targeted therapeutics. Par-4 was first identified in prostate cancer cells undergoing apoptosis. Both intracellular and extracellular Par-4 have been implicated in apoptosis. Relatively little is known about the role of Par-4 in breast cancer cell apoptosis. In this study, we sought to investigate the effects of Par-4 expression on cell proliferation, apoptosis and drug sensitivity in breast cancer cells. MCF-7 cells were stably transfected with expression vectors for Par-4, or transiently transfected with siRNA for Par-4 knockdown. Cell proliferation assays were performed using MTT and apoptosis was evaluated using acridine orange staining, fluorescence microscopy and flow cytometry. Par-4 overexpression reduced MCF-7 proliferation rates. Conversely, Par-4 knockdown led to increased MCF-7 proliferation. Par-4 downregulation also led to increased BCL-2 and reduced BID expression. Par-4 overexpression did not affect the cell cycle profile. However, MCF-7 cells with increased Par-4 expression showed reduced ERK phosphorylation, suggesting that the inhibition of cell proliferation promoted by Par-4 may be mediated by the MAPK/ERK1/2 pathway. MCF-7 cells with increased Par-4 expression showed a marginal increase in early apoptotic cells. Importantly, we found that Par-4 expression modulates apoptosis in response to docetaxel in MCF7 breast cancer cells. Par-4 exerts growth inhibitory effects on breast cancer cells and chemosensitizes them to docetaxel.

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Insulin-like growth factor-1 and 17β-estradiol down-regulate prostate apoptosis response-4 expression in MCF-7 breast cancer cells

Cited by 8 publications

References 13 publications

Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells

Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells

Chemoresistance and targeted therapies in ovarian and endometrial cancers

Prostate apoptosis response-4 is involved in the apoptosis response to docetaxel in MCF-7 breast cancer cells

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