Thyroid hormone induces cellular senescence in prostate cancer cells through induction of DEC1

Kotolloshi, Roland; Mirzakhani, Kimia; Ahlburg, Joana; Kraft, Florian; Pungsrinont, Thanakorn; Baniahmad, Aria

doi:10.1016/j.jsbmb.2020.105689

Cited by 14 publications

(10 citation statements)

References 41 publications

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“…An activation of these pathways leads to the inhibition of cyclin-CDK complexes, thereby inducing hypophosphorylation of the retinoblastoma tumor suppressor protein (pRb) to enhance E2F-interaction and inhibition of E2F target genes that drive cell cycle progression [ 48 ]. Other senescence-inducing side-pathways also exist and may include PML, DEC1, mTOR and autophagy, or other factors interacting with the AR such as the inhibitor of growth family ING1 and ING2 [ 31 , 32 , 38 , 49 , 50 , 51 ]. Another mechanism which has been implicated with cellular senescence is autophagy [ 52 , 53 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Kokal

Mirzakhani

Pungsrinont

et al. 2020

Cancers

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The androgen receptor (AR) plays a leading role in the control of prostate cancer (PCa) growth. Interestingly, structurally different AR antagonists with distinct mechanisms of antagonism induce cell senescence, a mechanism that inhibits cell cycle progression, and thus seems to be a key cellular response for the treatment of PCa. Surprisingly, while physiological levels of androgens promote growth, supraphysiological androgen levels (SAL) inhibit PCa growth in an AR-dependent manner by inducing cell senescence in cancer cells. Thus, oppositional acting ligands, AR antagonists, and agonists are able to induce cellular senescence in PCa cells, as shown in cell culture model as well as ex vivo in patient tumor samples. This suggests a dual AR-signaling dependent on androgen levels that leads to the paradox of the rational to keep the AR constantly inactivated in order to treat PCa. These observations however opened the option to treat PCa patients with AR antagonists and/or with androgens at supraphysiological levels. The latter is currently used in clinical trials in so-called bipolar androgen therapy (BAT). Notably, cellular senescence is induced by AR antagonists or agonist in both androgen-dependent and castration-resistant PCa (CRPC). Pathway analysis suggests a crosstalk between AR and the non-receptor tyrosine kinase Src-Akt/PKB and the PI3K-mTOR-autophagy signaling in mediating AR-induced cellular senescence in PCa. In this review, we summarize the current knowledge of therapeutic induction and intracellular pathways of AR-mediated cellular senescence.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Kokal

Mirzakhani

Pungsrinont

et al. 2020

Cancers

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“…When the effect of LncRNA-ES3 was studied in high glucose-induced senescence of vascular smooth muscle cells (HA-VSMCs), researchers found that the expression of BHLHE40 was decreased significantly in HA-VSMCs, and overexpression of BHLHE40 alleviated senescence of HA-VSMCs [ 38 ]. While some studies reported that hypothyroidism might contribute to extended lifespan of humans, a recent study indicated that BHLHE40 was responsive to triiodothyronine (T3), suggesting that BHLHE40 could be a novel target gene for the thyroid hormone receptor and play an important role in cell aging [ 39 ]. Our research has shown that BHLHE40 was significantly up-regulated in EIF5A2-OE cells, thus we assumed that BHLHE40 might be a potential target by which EIF5A2 influenced aging.…”

Section: Discussionmentioning

confidence: 99%

EIF5A2 specifically regulates the transcription of aging-related genes in human neuroblastoma cells

Liu

Chen

et al. 2023

BMC Geriatr

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Background Post-transcriptional regulation plays a critical role in controlling biological processes such as aging. Previous studies have shown that eukaryotic initiation factor 5A (EIF5A) might play a crucial role in aging. It is unknown whether EIF5A2, a second isoform of EIF5A, could impact aging through post-transcriptional regulation. Methods In the present study, EIF5A2 overexpression (EIF5A2-OE) was induced in SH-SY5Y cells. RNA-seq, bioinformatics analysis and RT-qPCR validation experiments were then performed to explore the molecular mechanism of EIF5A2-mediated transcriptional regulation. Cell viability, proportion of senescent cells and the cell cycle were respectively determined by Cell Counting Kit-8, SA-β‑galactosidase and flow cytometry to evaluate the cell senescence. Results A total of 190 downregulated and 126 upregulated genes related to EIF5A2-OE were identified. Genes closely related to cellular aging processes such as unfolded protein response (UPR), cell adhesion and calcium signaling pathway were under global transcriptional regulation. Moreover, EIF5A2-OE promoted the viability of SH-SY5Y cells and reduced cell senescence in vitro. Among 30 genes with the most significant expression differences in EIF5A2-OE cells, we identified eight genes, including ASNS, ATF3, ATF4, CEBPB, DDIT3, HERPUD1, HSPA5 and XBP1, enriched in the UPR. Through EIF5A2-tanscription factors (TFs)-targets regulation network in EIF5A2-OE cells, we found three TFs, BHLHE40, RHOXF1 and TBX20, that targeted at these eight UPR-related genes. Verification test via the published database of human glial cell tissue showed only BHLHE40 and RHOXF1 were significantly associated with EIF5A2. Conclusions Our findings suggest that EIF5A2 may alleviate cell senescence in vitro and mediate UPR-related genes via specific TFs. Thus, EIF5A2 could function as a regulator of aging via the regulation of transcription, which greatly expands the current understanding of the mechanisms of EIF5A2-mediated gene regulation.

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“…These effects have been explained by a functional TRE site in the PSA gene promoter, which is transactivated in the presence of androgens ( 44 ). On the other hand, studies carried out in LNCaP cells showed that T3 induces senescence (increase in BHLHE40) and cell arrest (increase in p15) in a dose-dependent manner in a range from 0.1 to 10 nM ( 45 ), and that 10 nM of T3 increases the levels of some metabolites, such as glycine, glutamate, creatine, and taurine ( 7 ). In contrast, T4 effects have been less studied.…”

Section: Biological Effects Of Thyroid Hormonesmentioning

confidence: 99%

Prostate gland as a target organ of thyroid hormones: advances and controversies

Anguiano

Delgado‐González

et al. 2022

Endocrine Connections

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Thyroid hormones are involved in the development and function of the male reproductive system, but their effects on the prostate have been poorly studied. This work reviews studies related to the interrelationship between the thyroid and prostate. The information presented here is based upon bibliographic searches in PubMed using the following search terms: prostate combined with thyroid hormone or triiodothyronine (T3), thyroxine (T4), hypothyroidism, hyperthyroidism, or deiodinase. We identified and searched 49 articles directly related to the issue, and discarded studies related to endocrine disruptors. The number of publications has grown in the last 20 years, considering that one of the first studies was published in 1965. This review provides information based on in vitro studies, murine models, and clinical protocols in patients with thyroid disorders. Studies indicate that thyroid hormones regulate different aspects of growth, metabolism, and prostate pathology, whose global effect depends on total and/or free concentrations of thyroid hormones in serum, local bioavailability and the endocrine androgen/thyronine context.

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Thyroid hormone induces cellular senescence in prostate cancer cells through induction of DEC1

Cited by 14 publications

References 41 publications

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

EIF5A2 specifically regulates the transcription of aging-related genes in human neuroblastoma cells

Prostate gland as a target organ of thyroid hormones: advances and controversies

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