Involvement of Akt isoforms in chemoresistance of endometrial carcinoma cells

Girouard, Julie; Lafleur, Marie-Judith; Parent, Stefan; Leblanc, Valérie; Asselin, Éric

doi:10.1016/j.ygyno.2012.11.016

Cited by 31 publications

(23 citation statements)

References 28 publications

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“…K8/18 knockdown increases Akt1 and Akt3 membrane targeting and activation. The predominant activity of Akt1 and Akt3 in cell motility and invasion is in agreement with our recent study showing that Akt2 blocks cell motility of endometrial carcinoma cells, whereas Akt1 and Akt3 increase wound closure (68). Because claudin1 silencing decreases the presence of phospho-Akt1 and Akt3 at the membrane, we propose that the localized accumulation of claudin1 generates specific membrane regions suitable for PI3K/Akt activation.…”

Section: Discussionsupporting

confidence: 92%

Keratin 8 and 18 Loss in Epithelial Cancer Cells Increases Collective Cell Migration and Cisplatin Sensitivity through Claudin1 Up-regulation

Fortier

Asselin

Cadrin

2013

Journal of Biological Chemistry

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195

141

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Background: Loss of keratins 8 and 18 (K8/18) is a hallmark of epithelial-mesenchymal transition (EMT), but its role in tumor progression is unclear. Results: Epithelial cancer cells depleted in K8/18 are more invasive and sensitive to cisplatin through the up-regulation of claudin1. Conclusion: K8/18 loss promotes collective cancer cell migration without inducing EMT. Significance: Cancer cell invasion can arise from K8/18 loss independently of EMT.

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Section: Discussionsupporting

confidence: 92%

Keratin 8 and 18 Loss in Epithelial Cancer Cells Increases Collective Cell Migration and Cisplatin Sensitivity through Claudin1 Up-regulation

Fortier

Asselin

Cadrin

2013

Journal of Biological Chemistry

Self Cite

195

141

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“…Downstream of PI3K, AKT isoforms (AKT1-2-3) have been reported to also increase the chemoresistance against platinum drugs, taxane and doxorubicin, in both ovarian and endometrial cancers [95–104]. It has been demonstrated that only AKT1 and AKT2 isoforms are responsible for the acquisition of resistance against cisplatin and paclitaxel while all three isoforms of AKT increase doxorubicin resistance in endometrial cancer cells [98]. Concerning ovarian cancer, it has been demonstrated that AKT2 expression increase resistance to cisplatin [105].…”

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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“…Studies using chemoresistant cell lines and RNAi have been conducted to assess the effect of individual AKT isoforms on drug resistance. Results have shown that while all three isoforms were necessary for optimal cell proliferation, apoptosis evasion, and cell survival, AKT2 was most crucial in chemoresistance (Girouard et al 2013); this is in accordance with previous studies which suggested that elevated AKT2 activation following cisplatin treatment was responsible for Bcl2 activation and reduced apoptosis (Rouette et al 2012). Finally, we have previously shown that AKT regulates PTGS2 expression in EC through the activation of the NFkB pathway; this, in turn, enables enhanced angiogenesis, tumor invasiveness, and potentially chemoresistance (St-Germain et al 2004a,b, Chaudhry & Asselin 2009).…”

Section: R91mentioning

confidence: 99%

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

Fabi¹,

Asselin²

2014

Reproduction

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The three isoforms of AKT: AKT1, AKT2, and AKT3, are crucial regulators of both normal and pathological cellular processes. Each of these isoforms exhibits a high level of homology and functional redundancy with each other. However, while being highly similar and structurally homologous, a rising amount of evidence is showing that each isoform possesses specific targets as well as preferential subcellular localization. The role of AKT has been studied extensively in reproductive processes, but isoform-specific roles are yet to be fully understood. This review will focus on the role of AKT in the uterus and its function in processes related to cell death and proliferation such as embryo implantation, decidualization, endometriosis, and endometrial cancer in an isoform-centric manner. In this review, we will cover the activation of AKT in various settings, localization of isoforms in subcellular compartments, and the effect of isoform expression on cellular processes. To fully understand the dynamic molecular processes taking place in the uterus, it is crucial that we better understand the physiological role of AKT isoforms as well as their function in the emergence of diseases.Reproduction (2014) 148 R85-R95

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Involvement of Akt isoforms in chemoresistance of endometrial carcinoma cells

Cited by 31 publications

References 28 publications

Keratin 8 and 18 Loss in Epithelial Cancer Cells Increases Collective Cell Migration and Cisplatin Sensitivity through Claudin1 Up-regulation

Keratin 8 and 18 Loss in Epithelial Cancer Cells Increases Collective Cell Migration and Cisplatin Sensitivity through Claudin1 Up-regulation

Chemoresistance and targeted therapies in ovarian and endometrial cancers

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

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