Correction to: The androgen receptor—lncRNASAT1-AKT-p15 axis mediates androgen-induced cellular senescence in prostate cancer cells

Mirzakhani, Kimia; Kallenbach, Julia; Rasa, Seyed Mohammad Mahdi; Ribaudo, Federico; Ungelenk, Martin; Ehsani, Marzieh; Gong, Wenrong; Gaßler, Nikolaus; Leeder, Mirjam; Grimm, Marc-Oliver; Neri, Francesco; Baniahmad, Aria

doi:10.1038/s41388-021-02125-5

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“…RNA-seq was performed and analyzed for an overlap of androgen-mediated upregulated genes in two cell lines, the androgen-dependent LNCaP and the castration-resistant C4-2 cell lines. In contrast to LAL treatment, SAL induces cellular senescence in both cell lines [ 9 ]. Interestingly, inhibition of AKT by AKTi represses androgen-induced cellular senescence.…”

Section: Resultsmentioning

confidence: 99%

“…RNA-sequencing and transcriptome analysis of both LNCaP and C4-2 cell lines were previously described [ 9 ]. Cells were treated for 3 days with DMSO and the AR-specific agonist R1881, with and without the AKT inhibitor (1 µM) AKTi, prior to RNA isolation.…”

Section: Methodsmentioning

confidence: 99%

“…LNCaP cells were seeded in RPMI 1640 medium containing 5% normal untreated FBS and cultured for 48 h. After 72 h of ligand treatment, cells were fixed with 4% paraformaldehyde and permeabilized with 0.25% Triton-X100/PBS [ 9 ] for 10 min at room temperature. After three washing steps in 1x PBS, a blocking solution (5% Normal Goat Serum/PBS) was added for 1 h. Primary antibodies were incubated in a humidified chamber overnight at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

“…The growth inhibition of PCa by AR antagonists is associated with induction of cellular senescence [ 4 , 5 , 6 , 7 ]. Interestingly, also at supraphysiological androgen level (SAL), the proliferation of PCa is inhibited and cellular senescence is induced, an irreversible cell cycle arrest [ 7 , 8 , 9 ]. Accordingly, cellular senescence is induced in PCa samples from patients treated ex vivo [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Similar results were obtained using dihydrotestosterone [ 8 ]. Furthermore, SAL treatment hyperphosphorylates AKT, induces p16 INK4A and p15 INK4b , reduces Cyclin D1, hypophosphorylates retinoblastoma protein (pRb) and enhances autophagy activity [ 8 , 9 ]. Using the AKT inhibitor (AKTi), the SAL-induced level of senescent cells was reduced in both castration-sensitive (LNCaP) and castration-resistant (C4-2) PCa cell lines [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Androgen-Induced MIG6 Regulates Phosphorylation of Retinoblastoma Protein and AKT to Counteract Non-Genomic AR Signaling in Prostate Cancer Cells

et al. 2022

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The bipolar androgen therapy (BAT) includes the treatment of prostate cancer (PCa) patients with supraphysiological androgen level (SAL). Interestingly, SAL induces cell senescence in PCa cell lines as well as ex vivo in tumor samples of patients. The SAL-mediated cell senescence was shown to be androgen receptor (AR)-dependent and mediated in part by non-genomic AKT signaling. RNA-seq analyses compared with and without SAL treatment as well as by AKT inhibition (AKTi) revealed a specific transcriptome landscape. Comparing the top 100 genes similarly regulated by SAL in two human PCa cell lines that undergo cell senescence and being counteracted by AKTi revealed 33 commonly regulated genes. One gene, ERBB receptor feedback inhibitor 1 (ERRFI1), encodes the mitogen-inducible gene 6 (MIG6) that is potently upregulated by SAL, whereas the combinatory treatment of SAL with AKTi reverses the SAL-mediated upregulation. Functionally, knockdown of ERRFI1 enhances the pro-survival AKT pathway by enhancing phosphorylation of AKT and the downstream AKT target S6, whereas the phospho-retinoblastoma (pRb) protein levels were decreased. Further, the expression of the cell cycle inhibitor p15INK4b is enhanced by SAL and ERRFI1 knockdown. In line with this, cell senescence is induced by ERRFI1 knockdown and is enhanced slightly further by SAL. Treatment of SAL in the ERRFI1 knockdown background enhances phosphorylation of both AKT and S6 whereas pRb becomes hypophosphorylated. Interestingly, the ERRFI1 knockdown does not reduce AR protein levels or AR target gene expression, suggesting that MIG6 does not interfere with genomic signaling of AR but represses androgen-induced cell senescence and might therefore counteract SAL-induced signaling. The findings indicate that SAL treatment, used in BAT, upregulates MIG6, which inactivates both pRb and the pro-survival AKT signaling. This indicates a novel negative feedback loop integrating genomic and non-genomic AR signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%