Immune escape of AKT overexpressing ovarian cancer cells

Hahne, Jens C.; Meyer, Susanne; Gambaryan, Stepan; Walter, Ulrich; Dietl, Johannes; Engel, Jörg B.; Hönig, Arnd

doi:10.3892/ijo.2013.1846

Cited by 13 publications

(36 citation statements)

References 28 publications

(37 reference statements)

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“…The efficiency of NK-cell mediated cell lysis differs between A2780 cells and the cisplatinum-resistant A2780cis cells. A2780cis cells are less accessible for NK-cell mediated killing [73,95]. This finding is in agreement with a report by Bellucci et al, using a lentiviral shRNA library targeting >1,000 human genes they identified 83 genes that promote target cell resistance to human NKcell-mediated killing [132].…”

Section: Role Of Akt Expression Level In Tumour Cells In Regard To Nksupporting

confidence: 91%

“…Furthermore, the epithelialmesenchymal-transformation, an important step for tumour metastasis, has been shown to be related to AKT activation [65]. Deregulation of components of the PI3K/AKT-cascade not only contributes to ovarian cancer development and tumourigenesis but also to chemotherapeutic drug and radiation resistance as it was recently shown [4,20,[66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81]. The sensitivity of cells to radiation and 5% [137] 35-50% (m) [138,139] 20% (m) [138] Rare 3% (m) 20% (a) [140] Table 2: Frequencies of specific mutations in PIK3CA.…”

Section: Effects Of Altered Pi3k/akt/mtor-signal Transduction Pathwaymentioning

confidence: 99%

“…The cisplatinum-resistant A2780cis cell line has been developed by chronic exposure of the parental cisplatinum-sensitive A2780 cell line to increasing concentrations of the chemotherapeutic agent [94]. These cell lines are excellent models for analyzing the molecular basis for cisplatinum resistance in ovarian cancer [72][73][74][95][96][97][98]. According to these studies AKT over-expression in ovarian cancer is at least one important reason for platinum resistance in this tumour entity [61,72,99].…”

Section: Effects Of Altered Pi3k/akt/mtor-signal Transduction Pathwaymentioning

confidence: 99%

“…According to these studies AKT over-expression in ovarian cancer is at least one important reason for platinum resistance in this tumour entity [61,72,99]. It was shown that AKT protein expression is strong increased in cisplatinum-resistant A2780cis cell line compared to the parental A2780 cell lines [72,73]. The platinum resistance in A2780cis cell line could be overcome by AKT down-regulation via siRNA [72].…”

Section: Effects Of Altered Pi3k/akt/mtor-signal Transduction Pathwaymentioning

confidence: 99%

“…Conversely, there is accumulating evidence that the PI3K/AKT/mTOR pathway is involved in the development of several malignant traits of cancer cells as well as their escape from immunity [128]. In some studies the interactions between cancer cells and natural-killer (NK)-cells have been enlightened [73,95,[129][130][131]. Modified FATAL assay was used for determining the killing efficiency of NK-cells in regard to ovarian cancer cell models in-vitro.…”

Section: Role Of Akt Expression Level In Tumour Cells In Regard To Nkmentioning

confidence: 99%

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Platinum-resistance and AKT Over-expression in Ovarian Cancer

Hahne¹

2015

Int J Gynecol Clin Pract

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Ovarian cancer is among the most common cause of cancer death and ranks first in the number of deaths each year in the field of gynaecological malignancies. This is due to its late diagnosis and the development of chemoresistance. Platinum derivates, including cisplatinum and carboplatinum in combination with paclitaxel, are the first-line chemotherapeutic agents. Platinum derivates intercalates irreversibly into the DNA and creates inter-and intra-strand DNA cross-links. During cell division, platinum-DNA-adducts block the replication machinery, inducing DNA damage and apoptosis. Nearly all patients respond to first line chemotherapy before it comes later to recurrence of the disease. At time of recurrence, tumours are usually more aggressive, form metastasis in secondary tissues and acquire resistance to conventional chemotherapeutics. Drug resistance is a common problem in tumour therapy not only restricted to ovarian cancer. This is characterized by gene mutations, increased DNA repair, reduced drug efficacy and enhanced drug clearance and detoxification. Up to now the complex molecular mechanism of chemoresistance is not well understood but increasing evidence points towards AKT over-expression and alteration of the PI3K/AKT/mTOR cascade as a central mechanistic reason for this resistance.

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Section: Role Of Akt Expression Level In Tumour Cells In Regard To Nksupporting

confidence: 91%

Section: Effects Of Altered Pi3k/akt/mtor-signal Transduction Pathwaymentioning

confidence: 99%

Section: Effects Of Altered Pi3k/akt/mtor-signal Transduction Pathwaymentioning

confidence: 99%

Section: Effects Of Altered Pi3k/akt/mtor-signal Transduction Pathwaymentioning

confidence: 99%

Section: Role Of Akt Expression Level In Tumour Cells In Regard To Nkmentioning

confidence: 99%

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Platinum-resistance and AKT Over-expression in Ovarian Cancer

Hahne¹

2015

Int J Gynecol Clin Pract

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Epigenetic‐mediated immune suppression of positive co‐stimulatory molecules in chemoresistant ovarian cancer cells

Çaçan

2017

Cell Biology International

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The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity. This study demonstrates that expression of positive co-stimulatory molecules, OX-40L and 4-1BBL, is suppressed while expression of immunosuppressive molecule programmed death ligand-1 (PD-L1/CD274) is enhanced in chemoresistant cells compared to parental chemosensitive ovarian cancer cells. Here, the molecular mechanisms of silencing of OX-40L and 4-1BBL expression were investigated in chemoresistant A2780-AD ovarian cancer cells. The suppression of OX-40L and 4-1BBL are due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to gene silencing during cancer progression. We identify important epigenetic regulators, histone deacetylase 1/3 (HDAC1/HDAC3) and DNA methyltransferase 1 (DNMT1), that exhibit aberrant association with OX-40L and 4-1BBL promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increase OX-40L and 4-1BBL expression in chemoresistant cells. This study suggests that loss of histone acetylation and accumulation of DNA methylation correlates with suppressed expression of OX-40L and 4-1BBL in chemoresistant ovarian cancer cells. This study marks the first report of the regulation of these two molecules by histone deacetylation and DNA methylation in chemoresistant ovarian cancer cells.

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