Expression, activation, and role of AKT isoforms in the uterus

Fabi, François; Asselin, Éric

doi:10.1530/rep-14-0270

Cited by 37 publications

(25 citation statements)

References 103 publications

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“…Par-4 activity is also linked to PTEN tumor suppressor activity since PTEN is a negative regulator of the PI3K pathway [24]. Due to the high mutation rate of PTEN in ovarian and endometrial cancers, PI3K is unrestrained, leading to a high AKT1 phosphorylation and subsequent inhibition of Par-4 activity which is related to chemoresistance [28, 29, 59, 60]. In the case of cl-Par-4, Wortmannin and NVP-BEZ235 inhibits PI3K upstream and downstream targets should be considered.…”

Section: Discussionmentioning

confidence: 99%

“…In turn, Par-4 is also known to negatively regulate the level/activity of AKT downstream targets such as NFκB and XIAP [25–27]. Data from cbioportal.org indicates that PI3K/AKT/PTEN pathway is more than often mutated or amplified in endometrial (>90%) and ovarian cancers (>55%), offering an advantage for cancer cell survival [28, 29]. These high levels of alteration in the PI3K/AKT/PTEN pathway indicate a potential issue for Par-4 activity, because of AKT1 negative regulation, in endometrial and ovarian cancers and are also known for being important key protein related to the chemoresistance of the feminine cancers [5, 6, 30–32].…”

Section: Introductionmentioning

confidence: 99%

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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: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Using TCGA datasets, it is possible to observe that major components of the PI3K/AKT pathway present a high frequency of alteration in gynecological cancers ( > 40% in ovaries; > 90% in the uterus) (Figure 2A) [92, 93]. These alterations of the PI3K pathway are involved in the tumorigenesis of gynecological tumors but also their chemoresistance profile.…”

Section: Chemoresistance In Gynecological Cancersmentioning

confidence: 99%

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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“…Further details can be found about decidualization and implantation processes in the following review [10]. Decidualization of stromal cells is induced through the concerted effect of cAMP and progesterone, or their respective analogs, 8-bromo-cyclic adenosine monophosphate (8-br-cAMP) and medroxyprogesterone acetate (MPA) [2, 11, 12].…”

Section: Introductionmentioning

confidence: 99%

Regulation of the PI3K/Akt pathway during decidualization of endometrial stromal cells

et al. 2017

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Infertility is constantly increasing in Canada, where 16% of Canadian couples are experiencing difficulty conceiving. It is thought that infertility can emanate from the dysregulated communication between the embryo and the maternal endometrium. In order to allow for this window of implantation to be open at the right moment, endometrial stromal cells proliferate and differentiate by a mechanism called decidualization. Intracellular and molecular mechanisms involved in the regulation of apoptosis and cell proliferation during decidualization of the endometrium are yet to be fully understood. It has been well demonstrated previously that Akt is importantly involved in cell survival and glycogen synthesis. Akt1, Akt2 and Akt3 isoforms have distinct physiological roles; this could also be the case during decidualization and pregnancy. The aim of this study is to investigate the regulation of PI3K/Akt pathway during the decidualization process of endometrial stromal cells. Expression of Akt isoforms, Akt activity (phospho-Akt), pIκB and substrates of Akt during decidualization were measured. To our knowledge, these results are the first to suggest a decrease in levels of Akt isoforms as well as a downregulation of Akt activity in the process of decidualization of human endometrial stromal cells. We also uncovered that decidualization induced nuclear localization of p65 through the phosphorylation of IκB, its inhibitory subunit; however, Par-4, a recently uncovered regulator of cell differentiation, was displaced from the nucleus upon decidualization. Our results also suggest that HIESC cells exhibit decreased motility during decidualization and that PI3K pathway inhibition could be involved in this process. Finally, we demonstrate that specific Akt isoforms present unique effects on the successful induction of decidualization. Further analyses will involve investigations to understand the precise signaling mechanisms by which this pathway is regulated.

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Expression, activation, and role of AKT isoforms in the uterus

Cited by 37 publications

References 103 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

Regulation of the PI3K/Akt pathway during decidualization of endometrial stromal cells

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