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dc.contributor.authorBerrak, Özge
dc.contributor.authorArısan, Elif Damla
dc.contributor.authorObakan Yerlikaya, Pınar
dc.contributor.authorÇoker Gürkan, Ajda
dc.contributor.authorPalavan Ünsal, Zeynep Narçın
dc.description.abstractPurvalanol and roscovitine are cyclin dependent kinase (CDK) inhibitors that induce cell cycle arrest and apoptosis in various cancer cells. We further hypothesized that co-treatment of CDK inhibitors with rapamycin, an mTOR inhibitor, would be an effective combinatory strategy for the inhibition of prostate cancer regard to androgen receptor (AR) status due to inhibition of proliferative pathway, PI3K/AKT/mTOR, and induction of cell death mechanisms. Androgen responsive (AR+), PTEN-/- LNCaP and androgen independent (AR-), PTEN+/- DU145 prostate cancer cells were exposed to purvalanol (20 A mu M) and roscovitine (30 A mu M) with or without rapamycin for 24 h. Cell viability assay, immunoblotting, flow cytometry and fluorescence microscopy was used to define the effect of CDK inhibitors with or without rapamycin on proliferative pathway and cell death mechanisms in LNCaP and DU145 prostate cancer cells. Co-treatment of rapamycin modulated CDK inhibitors-induced cytotoxicity and apoptosis that CDK inhibitors were more potent to induce cell death in AR (+) LNCaP cells than AR (-) DU145 cells. CDK inhibitors in the presence or absence of rapamycin induced cell death via modulating upstream PI3K/AKT/mTOR signaling pathway in LNCaP cells, exclusively only treatment of purvalanol have strong potential to inhibit both upstream and downstream targets of mTOR in LNCaP and DU145 cells. However, co-treatment of rapamycin with CDK inhibitors protects DU145 cells from apoptosis via induction of autophagy mechanism. We confirmed that purvalanol and roscovitine were strong apoptotic and autophagy inducers that based on regulation of PI3K/AKT/mTOR signaling pathway. Co-treatment of rapamycin with purvalanol and roscovitine exerted different effects on cell survival and death mechanisms in LNCaP and DU145 cell due to their AR receptor status. Our studies show that co-treatment of rapamycin with CDK inhibitors inhibit prostate cancer cell viability more effectively than either agent alone, in part, by targeting the mTOR signaling cascade in AR (+) LNCaP cells. In this point, mTOR is a fine-tuning player in purvalanol and roscovitine-induced apoptosis and autophagy via regulation of PI3K/AKT and the downstream targets, which related with cell proliferation.tr_TR
dc.publisherSpringer, Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlandstr_TR
dc.subjectCyclin-Dependent Kinasetr_TR
dc.subjectMammalian Targettr_TR
dc.subjectAndrogen Receptortr_TR
dc.subjectInduced Apoptosistr_TR
dc.subjectTranscription Factorstr_TR
dc.subjectMediated Apoptosistr_TR
dc.titlemTOR is a fine tuning molecule in CDK inhibitors-induced distinct cell death mechanisms via PI3K/AKT/mTOR signaling axis in prostate cancer cellstr_TR

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