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Review
. 2023 Jul 5;24(13):11100.
doi: 10.3390/ijms241311100.

Targeting Prostate Cancer, the 'Tousled Way'

Siddhant Bhoir  1 , Arrigo De Benedetti  1
Affiliations
Review

Targeting Prostate Cancer, the 'Tousled Way'

Siddhant Bhoir et al. Int J Mol Sci. .

Abstract

Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas associated with a poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained underrepresented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.

Keywords: ADT; AR; PCa; TLK1 signaling; and pathway inhibition.

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Conflict of interest statement

Both authors are named inventors in a patent on J54: US 2020/0306258 A1 “Targeting the TLK1/NEK1 axis in Prostate Cancer.” No conflicts of interests currently exist.

Figures

Figure 1
Figure 1
Progression and recurrence of prostate cancer measured biochemically (PSA). Created with BioRender.com.
Figure 3
Figure 3
Top. Cell cycle analysis by PI-FACS of human LNCaP and mouse TRAMP-C2 cells treated with Bicalutamide (BIC), J54, or combination (5 μM each). Likewise, LNCaP cells expressing a dominant TLK1-Kinase, Dead, when treated with BIC, arrest instead in G2, followed by apoptosis after 36 h [110]. FACS analysis was carried out as described in [20]. Bottom. (A) Cell cycle analysis by PI-FACS of LNCaP cells treated with Enzalutamide (ENZ), J54, or a combination (5 μM each). (B) Apoptotic ladder in ENZ or BIC+J54 for 48 h, which was generated as described in Apoptosis DNA fragmentation analysis protocol|Abcam.
Figure 2
Figure 2
TLK1 plays multiple crucial roles in prostate cancer progression and therapy resistance. Here, we describe the various mechanisms by which TLK1 contributes to these processes. (1) ADT triggers the activation of mTORC1, which activates 4EBP1, causing the release of eIF4E. Excess eIF4E initiates the translation of TLK1B. (2) TLK1/1B, once produced, activates NEK1 by phosphorylating it at T141. Activated NEK1 activates the ATR-Chk1 DDR signaling cascade. The activation of DDR promotes DNA repair, which aids in the resistance to DNA-damaging therapeutic agents. (3) Through TLK1-NEK1 signaling, YAP is phosphorylated on Y407 and T493 residues, stabilizing it. This phosphorylated YAP binds to TEAD or other transcription factors (TF) and relocates to the nucleus, evading proteasomal degradation. The accumulation and stabilization of YAP contribute to the progression of CRPC and resistance to drugs. (4) The TLK1-NEK1 axis also plays a role in phosphorylating VDAC1 at S193, which helps maintain the integrity of the mitochondrial membrane and inhibits intrinsic apoptotic signaling. (5) TLK1 directly phosphorylates AKTIP on T22 and S237 residues, activating AKT. This activation of AKT promotes pro-survival and pro-migratory signaling. (6) TLK1 also interacts with and phosphorylates MK5, enhancing its catalytic activity towards HSP27, a substrate of MK5. This increased activity of MK5 leads to enhanced prostate cancer cell migration, invasion, and metastasis. Created with BioRender.com.
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