biostudies-literatureMirzakhani KDeutsche Krebshilfe943-959https://www.ebi.ac.uk/biostudies/studies/S-EPMC8837536biostudies-literatureUnknown41(7)The bipolar androgen therapy (BAT) to treat prostate cancer (PCa) includes cycles of supraphysiological androgen levels (SAL) under androgen-deprivation therapy (ADT). We showed previously that SAL induces cellular senescence in androgen-sensitive PCa cells and in ex vivo-treated patient PCa tumor samples. Here, we analyzed the underlying molecular pathway and reveal that SAL induces cellular senescence in both, castration-sensitive (CSPC) LNCaP and castration-resistant PCa (CRPC) C4-2 cells through the cell cycle inhibitor p15^INK4b and increased phosphorylation of AKT. Treatment with the AKT inhibitor (AKTi) potently inhibited SAL-induced expression of p15^INK4b and cellular senescence in both cell lines. Proximity-ligation assays (PLA) combined with high-resolution lOncogeneThe androgen receptor-lncRNASAT1-AKT-p15 axis mediates androgen-induced cellular senescence in prostate cancer cells.PMC883753670113814Rasa SMMMirzakhani KGassler NEhsani MLeeder MNeri FUngelenk MGrimm MOKallenbach JRibaudo FGong WBaniahmad AfalseThe androgen receptor-lncRNASAT1-AKT-p15 axis mediates androgen-induced cellular senescence in prostate cancer cells.The bipolar androgen therapy (BAT) to treat prostate cancer (PCa) includes cycles of supraphysiological androgen levels (SAL) under androgen-deprivation therapy (ADT). We showed previously that SAL induces cellular senescence in androgen-sensitive PCa cells and in ex vivo-treated patient PCa tumor samples. Here, we analyzed the underlying molecular pathway and reveal that SAL induces cellular senescence in both, castration-sensitive (CSPC) LNCaP and castration-resistant PCa (CRPC) C4-2 cells through the cell cycle inhibitor p15^INK4b and increased phosphorylation of AKT. Treatment with the AKT inhibitor (AKTi) potently inhibited SAL-induced expression of p15^INK4b and cellular senescence in both cell lines. Proximity-ligation assays (PLA) combined with high-resolution l2022-01-01T00:00:00Z2022 Feb2025-04-04T13:21:29.719Z2025-04-04T13:21:29.719ZS-EPMC88375363466727610.1038/s41388-021-02060-5