Papers by Julia Kallenbach
Cancers
The human telomerase is a key factor during tumorigenesis in prostate cancer (PCa). The androgen ... more The human telomerase is a key factor during tumorigenesis in prostate cancer (PCa). The androgen receptor (AR) is a key drug target controlling PCa growth and regulates hTERT expression, but is described to either inhibit or to activate. Here, we reveal that androgens repress and activate hTERT expression in a concentration-dependent manner. Physiological low androgen levels activate, while, notably, supraphysiological androgen levels (SAL), used in bipolar androgen therapy (BAT), repress hTERT expression. We confirmed the SAL-mediated gene repression of hTERT in PCa cell lines, native human PCa samples derived from patients treated ex vivo, as well as in cancer spheroids derived from androgen-dependent or castration resistant PCa (CRPC) cells. Interestingly, chromatin immuno-precipitation (ChIP) combined with functional assays revealed a positive (pARE) and a negative androgen response element (nARE). The nARE was narrowed down to 63 bp in the hTERT core promoter region. AR and tum...
Biomolecules, Jul 29, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
International Journal of Molecular Sciences, Oct 14, 2021
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Cells, Nov 16, 2021
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Cell & Bioscience
Background Prostate cancer (PCa) is an age-related malignancy in men with a high incidence rate. ... more Background Prostate cancer (PCa) is an age-related malignancy in men with a high incidence rate. PCa treatments face many obstacles due to cancer cell resistance and many bypassing mechanisms to escape therapy. According to the intricacy of PCa, many standard therapies are being used depending on PCa stages including radical prostatectomy, radiation therapy, androgen receptor (AR) targeted therapy (androgen deprivation therapy, supraphysiological androgen, and AR antagonists) and chemotherapy. Most of the aforementioned therapies have been implicated to induce cellular senescence. Cellular senescence is defined as a stable cell cycle arrest in the G1 phase and is one of the mechanisms that prevent cancer proliferation. Results In this review, we provide and analyze different mechanisms of therapy-induced senescence (TIS) in PCa and their effects on the tumor. Interestingly, it seems that different molecular pathways are used by cancer cells for TIS. Understanding the complexity and ...
Cancer Cell International
Naturally, in somatic cells chromosome ends (telomeres) shorten during each cell division. This p... more Naturally, in somatic cells chromosome ends (telomeres) shorten during each cell division. This process ensures to limit proliferation of somatic cells to avoid malignant proliferation; however, it leads to proliferative senescence. Telomerase contains the reverse transcriptase TERT, which together with the TERC component, is responsible for protection of genome integrity by preventing shortening of telomeres through adding repetitive sequences. In addition, telomerase has non-telomeric function and supports growth factor independent growth. Unlike somatic cells, telomerase is detectable in stem cells, germ line cells, and cancer cells to support self-renewal and expansion. Elevated telomerase activity is reported in almost all of human cancers. Increased expression of hTERT gene or its reactivation is required for limitless cellular proliferation in immortal malignant cells. In hormonally regulated tissues as well as in prostate, breast and endometrial cancers, telomerase activity ...
Biomolecules
The bipolar androgen therapy (BAT) includes the treatment of prostate cancer (PCa) patients with ... more 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 pathwa...
Oncogene, 2021
The original article has been corrected. Open Access This article is licensed under a Creative Co... more The original article has been corrected. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in anymedium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
Oncogene, 2021
The bipolar androgen therapy (BAT) to treat prostate cancer (PCa) includes cycles of supraphysiol... more 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 p15INK4b and increased phosphorylation of AKT. Treatment with the AKT inhibitor (AKTi) potently inhibited SAL-induced expression of p15INK4b and cellular senescence in both cell lines. Proximity-ligation assays (PLA) combined with high-resolution laser-scanning microscopy indicate that SAL promotes interaction of endogenous androgen receptor (AR) with AKT in the cytoplasm as well as in the nucleus detectable after three days. Transcriptome sequencing (RNA-seq) co...
Biomolecules, 2021
Inhibitor of growth 3 (ING3) is one of five members of the ING tumour suppressor family, characte... more Inhibitor of growth 3 (ING3) is one of five members of the ING tumour suppressor family, characterized by a highly conserved plant homeodomain (PHD) as a reader of the histone mark H3K4me3. ING3 was reported to act as a tumour suppressor in many different cancer types to regulate apoptosis. On the other hand, ING3 levels positively correlate with poor survival prognosis of prostate cancer (PCa) patients. In PCa cells, ING3 acts rather as an androgen receptor (AR) co-activator and harbours oncogenic properties in PCa. Here, we show the identification of a novel ING3 splice variant in both the human PCa cell line LNCaP and in human PCa patient specimen. The novel ING3 splice variant lacks exon 11, ING3∆ex11, which results in deletion of the PHD, providing a unique opportunity to analyse functionally the PHD of ING3 by a natural splice variant. Functionally, overexpression of ING3Δex11 induced morphological changes of LNCaP-derived 3D spheroids with generation of lumen and pore-like st...
Cells
The androgen receptor (AR) is a member of the nuclear receptor superfamily and has three function... more The androgen receptor (AR) is a member of the nuclear receptor superfamily and has three functional domains, namely the N-terminal, DNA binding, and C-terminal domain. The N-terminal domain harbors potent transactivation functions, whereas the C-terminal domain binds to androgens and antiandrogens used to treat prostate cancer. AR has genomic activity being DNA binding-dependent or through interaction with other DNA-bound transcription factors, as well as a number of non-genomic, non-canonical functions, such as the activation of the ERK, AKT, and MAPK pathways. A bulk of evidence indicates that non-coding RNAs have functional interactions with AR. This type of interaction is implicated in the pathogenesis of human malignancies, particularly prostate cancer. In the current review, we summarize the available data on the role of microRNAs, long non-coding RNAs, and circular RNAs on the expression of AR and modulation of AR signaling, as well as the effects of AR on their expression. R...
International Journal of Molecular Sciences
Androgen deprivation therapy (ADT) and androgen receptor (AR)-targeted therapy are the gold stand... more Androgen deprivation therapy (ADT) and androgen receptor (AR)-targeted therapy are the gold standard options for treating prostate cancer (PCa). These are initially effective, as localized and the early stage of metastatic disease are androgen- and castration-sensitive. The tumor strongly relies on systemic/circulating androgens for activating AR signaling to stimulate growth and progression. However, after a certain point, the tumor will eventually develop a resistant stage, where ADT and AR antagonists are no longer effective. Mechanistically, it seems that the tumor becomes more aggressive through adaptive responses, relies more on alternative activated pathways, and is less dependent on AR signaling. This includes hyperactivation of PI3K-AKT-mTOR pathway, which is a central signal that regulates cell pro-survival/anti-apoptotic pathways, thus, compensating the blockade of AR signaling. The PI3K-AKT-mTOR pathway is well-documented for its crosstalk between genomic and non-genomic...
Cancers
The human telomerase is a key factor during tumorigenesis in prostate cancer (PCa). The androgen ... more The human telomerase is a key factor during tumorigenesis in prostate cancer (PCa). The androgen receptor (AR) is a key drug target controlling PCa growth and regulates hTERT expression, but is described to either inhibit or to activate. Here, we reveal that androgens repress and activate hTERT expression in a concentration-dependent manner. Physiological low androgen levels activate, while, notably, supraphysiological androgen levels (SAL), used in bipolar androgen therapy (BAT), repress hTERT expression. We confirmed the SAL-mediated gene repression of hTERT in PCa cell lines, native human PCa samples derived from patients treated ex vivo, as well as in cancer spheroids derived from androgen-dependent or castration resistant PCa (CRPC) cells. Interestingly, chromatin immuno-precipitation (ChIP) combined with functional assays revealed a positive (pARE) and a negative androgen response element (nARE). The nARE was narrowed down to 63 bp in the hTERT core promoter region. AR and tum...
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Papers by Julia Kallenbach