The cdk1-cyclin B complex is involved in everolimus triggered resistance in the PC3 prostate cancer cell line

Tsaur, Igor; Makarević, Jasmina; Hudak, Lukasz; Juengel, Eva; Kurosch, M.; Wiesner, Christoph; Bartsch, Georg; Harder, Sebastian; Haferkamp, Axel; Blaheta, Roman A.

doi:10.1016/j.canlet.2011.08.026

Cited by 43 publications

(35 citation statements)

References 36 publications

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“…Such a shift has also been observed during lung cancer drug resistance with an accelerated G2/M-phase transition [16]. In prostate cancer cells everolimus resistance has also revealed a higher G2/M-phase cell cycle fraction [7]. Based on a recent study, chronic everolimus application to RCC cells resulted in an accumulation of G2/M-phase cells [6].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, low expression of cdk2 and cyclin A has been shown to be associated with cell cycle arrest and accumulation of cells in the S-phase [27]. Everolimus resistance has also been associated with a considerable increase in cdk2 in prostate cancer [7] and in RCC cells [6]. Thus, augmented cdk2 seems closely related to non-responsiveness towards everolimus and deserves attention in overcoming resistance development.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been shown that chronic mTOR-inhibition evokes undesired feedback mechanisms in RCC cells, which may lead to resistance development [5,6]. Undesirable feedback has also been demonstrated in prostate cancer cells after chronic exposure to everolimus, indicating molecular alterations tied to acquired resistance [7]. Agents targeting such feedback loops and cross talk with other pathways involved in acquired resistance to mTOR-inhibition are, therefore, urgently required [8].…”

Section: Introductionmentioning

confidence: 99%

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HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A

et al. 2014

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BackgroundTargeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development.MethodsFunctional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins.ResultsEverolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A.ConclusionIt is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A

et al. 2014

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“…In the current experiments, knocking down cdk2 or cyclin A led to a substantial reduction of the tumor cell number, indicating the clinical relevance of both proteins for bladder cancer. Since cdks and cyclins are enhanced when drug resistance develops [28], [29], counteracting this process might be a potent strategy to prevent or overcome resistance [29]. During the last years, several novel therapeutic strategies have been designed to target cdks.…”

Section: Discussionmentioning

confidence: 99%

Amygdalin Blocks Bladder Cancer Cell Growth In Vitro by Diminishing Cyclin A and cdk2

et al. 2014

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Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25–10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR) related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug.

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“…While rapamycin specifically targets mTORC1, p70S6K is only one substrate of this mTOR complex. As a result of suppressing multiple downstream mediators involved in a variety of cellular functions, development of resistance to rapamycin or its other mTOR inhibitor derivatives has been reported 91 92. There is evidence that activation of the mTOR/p70S6K axis may participate in a negative feedback loop that inhibits PI3K/Akt in some circumstances.…”

Section: Impact Of P70s6k Inhibitionmentioning

confidence: 99%

p70 Ribosomal protein S6 kinase (Rps6kb1): an update

et al. 2014

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The Rps6kb1 gene encodes the 70 kDa ribosomal protein S6 kinase (p70S6K), which is a serine/threonine kinase regulated by phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. p70S6K plays a crucial role in controlling cell cycle, growth and survival. The PI3K/mTOR signalling pathway is one of the major mechanisms for controlling cell survival, proliferation and metabolism and is the central regulator of translation of some components of protein synthesis system. Upon activation, this kinase phosphorylates S6 protein of ribosomal subunit 40S resulting in selective translation of unique family of mRNAs that contain oligopyrimidine tract on 5' transcriptional site (5'TOP). 5'TOP mRNAs are coding the components of translational apparatus including ribosomal proteins and elongation factors. Due to the role of p70S6K in protein synthesis and also its involvement in a variety of human diseases ranging from diabetes and obesity to cancer, p70S6K is now being considered as a new therapeutic target for drug development. Furthermore, p70S6K acts as a biomarker for response to immunosuppressant as well as anticancer effects of inhibitors of the mTOR. Because of the narrow therapeutic index of mTOR inhibitors, drug monitoring is essential, and this is usually done by measuring blood drug levels, therapeutic response and drug-induced adverse effects. Recent studies have suggested that plasma p70S6K is a reliable index for the monitoring of patient response to mTOR inhibitors. Therefore, a better understanding of p70S6K and its role in various pathological conditions could enable the development of strategies to aid diagnosis, prognosis and treatment schedules.

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The cdk1-cyclin B complex is involved in everolimus triggered resistance in the PC3 prostate cancer cell line

Cited by 43 publications

References 36 publications

HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A

HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A

Amygdalin Blocks Bladder Cancer Cell Growth In Vitro by Diminishing Cyclin A and cdk2

p70 Ribosomal protein S6 kinase (Rps6kb1): an update

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