Tousled-like kinase 1: a novel factor with multifaceted role in mCRPC progression and development of therapy resistance

Khalil, Md Imtiaz; Benedetti, Arrigo De

doi:10.20517/cdr.2021.109

Cited by 16 publications

(23 citation statements)

References 59 publications

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Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

“…Upon development of castration-resistance, prostate cancer growth is, at least in part, achieved through mTOR activation and consequent upregulation of TLK1B [ 121 ]. The molecular mechanism was explored by Khalil and Benedetti who found that ADT inhibits the AR signaling pathway by blocking the nuclear relocation of AR, resulting in downregulation of the androgen-responsive gene FKBP5 , which controls intracellular glucocorticoid signaling and holds an important role in stress response modulation [ 121 ]. This, subsequently, leads to AKT and mTORC1 activation, which results in activation of eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and upregulation of the master eukaryotic translation switch eIF4E [ 121 ], which, in turn, initiates TLK1B translation.…”

Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

“…This, subsequently, leads to AKT and mTORC1 activation, which results in activation of eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and upregulation of the master eukaryotic translation switch eIF4E [ 121 ], which, in turn, initiates TLK1B translation. TLK1B phosphorylates NEK1, thereby triggering the ATR-CHK1-DDR signaling cascade [ 121 ]. Khalil and Benedetti suggested that activation of the DDR pathway through the TLK1-NEK1-ATR-CHK1 axis may be directly involved in the progression of CRPC [ 121 ].…”

Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

“…TLK1B phosphorylates NEK1, thereby triggering the ATR-CHK1-DDR signaling cascade [ 121 ]. Khalil and Benedetti suggested that activation of the DDR pathway through the TLK1-NEK1-ATR-CHK1 axis may be directly involved in the progression of CRPC [ 121 ].…”

Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

“…Specifically, YAP/TAZ represent phosphorylation targets of NEK1, an important step in YAP/TAZ stabilization and nuclear accumulation [ 122 , 123 ]. In more detail, TLK1-NEK1-dependent phosphorylation of YAP/TAZ facilitates YAP/TAZ binding to TEAD or other transcription factors resulting in the transcription of pro-proliferative genes, a process fostering CRPC progression [ 121 ].…”

Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

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Interplay of Developmental Hippo–Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer

Mourkioti

Angelopoulou

Belogiannis

et al. 2022

Cells

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Prostate cancer belongs in the class of hormone-dependent cancers, representing a major cause of cancer incidence in men worldwide. Since upon disease onset almost all prostate cancers are androgen-dependent and require active androgen receptor (AR) signaling for their survival, the primary treatment approach has for decades relied on inhibition of the AR pathway via androgen deprivation therapy (ADT). However, following this line of treatment, cancer cell pools often become resistant to therapy, contributing to disease progression towards the significantly more aggressive castration-resistant prostate cancer (CRPC) form, characterized by poor prognosis. It is, therefore, of critical importance to elucidate the molecular mechanisms and signaling pathways underlying the progression of early-stage prostate cancer towards CRPC. In this review, we aim to shed light on the role of major signaling pathways including the DNA damage response (DDR) and the developmental Hippo and Notch pathways in prostate tumorigenesis. We recapitulate key evidence demonstrating the crosstalk of those pathways as well as with pivotal prostate cancer-related ‘hubs’ such as AR signaling, and evaluate the clinical impact of those interactions. Moreover, we attempt to identify molecules of the complex DDR–Hippo–Notch interplay comprising potentially novel therapeutic targets in the battle against prostate tumorigenesis.

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Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

Section: Interplay Of Ddr/hippo/notch Pathways In Prostate Cancermentioning

confidence: 99%

See 3 more Smart Citations

Interplay of Developmental Hippo–Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer

Mourkioti

Angelopoulou

Belogiannis

et al. 2022

Cells

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TLK1-mediated RAD54 phosphorylation spatio-temporally regulates Homologous Recombination Repair

Ghosh

Kwon²,

Shabestari³

et al. 2022

Preprint

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Environmental agents like ionizing radiation (IR) and chemotherapeutic drugs can cause severe damage to the DNA, often in the form of double-strand breaks (DSBs). Remaining unrepaired, DSBs can lead to chromosomal rearrangements, and cell death. One major error-free pathway to repair DSBs is homologous recombination repair (HRR). Tousled-like kinase 1 (TLK1), a Ser/Thr kinase that regulates the DNA damage checkpoint, has been found to interact with RAD54, a central DNA translocase in HRR. To determine how TLK1 regulates RAD54, we inhibited or depleted TLK1 and tested how this impacts HRR in human cells using a ISce-I-DsRed fused reporter endonuclease. Our results show that TLK1 phosphorylates RAD54 at three threonines (T41, 59, and 700), of which 2 are located within its N-terminal domain (NTD) and one is located within its C-terminal domain (CTD). Phosphorylation at both T41 and T59 supports gene conversion and protects cells from DNA DSB damage. In contrast, phosphorylation of T700 leads to impaired gene conversion and engenders no protection to cells from cytotoxicity and rather results in repair delay. Further, our work enlightens the effect of RAD54-T700 (RAD54-CTD) phosphorylation by TLK1 in mammalian system and reveals a new site of interaction with RAD51.

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The TLK1-MK5 axis regulates motility, invasion, and metastasis of prostate cancer cells

Khalil

Benedetti

2022

Preprint

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Background: Metastatic dissemination of prostate cancer (PCa) accounts for majority of PCa related deaths. However, the exact mechanism of PCa cell spread is still unknown. We uncovered a novel interaction between two unrelated promotility factors, tousled-like kinase 1 (TLK1) and MAPK-activated protein kinase 5 (MK5), which initiates a signaling cascade promoting metastasis. In PCa, TLK1-MK5 signaling might be crucial as androgen deprivation therapy (ADT) leads to increased expression of both TLK1 and MK5 in metastatic patients, but in this work, we directly investigated the motility, invasive, and metastatic capacity of PCa cells following impairment of the TLK1>MK5 axis. Results: We conducted scratch wound repair and 3D invasion assays with LNCaP and PC3 cells to determine if TLK1 and MK5 can regulate motility and invasion. Both genetic depletion and pharmacologic inhibition of TLK1 and MK5 resulted in reduced migration and invasion through a Matrigel plug. We further elucidated the potential mechanisms underlying these effects and found that that this is likely due to reorganization of the actin fibers at lamellipodia and the focal adhesions network, in conjunction with increased expression of some MMPs that can affect penetration through the ECM. PC3, a highly metastatic cell line when assayed in xenografts, was further tested in tail-vein injection/lung metastasis model, and we showed that following inoculation, treatment with GLPG (MK5 specific inhibitor) or J54 (TLK1 inhibitor) the resulting lung tumor nodules were greatly diminished in number, and for J54 also in size. Conclusion: Our data support that TLK1-MK5 axis is functionally involved in driving PCa cell metastasis and clinical aggressiveness, hence, disruption of this axis may inhibit the metastatic capacity of PCa.

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Tousled-like kinase 1: a novel factor with multifaceted role in mCRPC progression and development of therapy resistance

Cited by 16 publications

References 59 publications

Interplay of Developmental Hippo–Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer

Interplay of Developmental Hippo–Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer

TLK1-mediated RAD54 phosphorylation spatio-temporally regulates Homologous Recombination Repair

The TLK1-MK5 axis regulates motility, invasion, and metastasis of prostate cancer cells

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