The TLK1-Nek1 axis promotes prostate cancer progression

Singh, Vibha; Jaiswal, Praveen Kumar; Ghosh, Ishita; Koul, Hari K.; Yu, Xiuping; Benedetti, Arrigo De

doi:10.1016/j.canlet.2019.03.041

Cited by 41 publications

(62 citation statements)

References 26 publications

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“…Recently, NEK1 has been linked to prostate cancer (PCa) by its function in DDR. Singh et al published two studies in a row demonstrating the role of the TLK1/NEK1 axis in PCa progression [65] and its pharmaceutical potential as a novel therapy combined with standard treatment [66]. The combined strategy of standard androgen-deprivation treatment (ADT) and thioridazine (TDH), a specific inhibitor of Tousled Like Kinases (TLK), inhibited an increase in the TLK1B prosurvival mechanism from PCa cells, leading to apoptosis.…”

Section: Nek1mentioning

confidence: 99%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.

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Section: Nek1mentioning

confidence: 99%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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“…The DDR is likely activated due to the role played by the AR as replication licensing factor ( Litvinov et al., 2006 ) in combination with the mTOR-dependent increased expression of TLK1B, which is highly dependent on the mTOR>4EBP1 pathway ( Sunavala-Dossabhoy et al., 2004 ), and resulting activation of the Nek1>ATR > Chk1 axis ( Singh et al., 2019a ). Additional work from our laboratory suggested that this may be a conserved nexus in additional cell models, in the TRAMP mouse, and probably in many patients, as the specific activating phosphorylation of Nek1 by TLK1 correlates with the Gleason score ( Singh et al., 2019b ). The resulting cell-cycle arrest is a survival mechanism for PCa cells, which remain quiescent until they reprogram and adapt to androgen-independent (AI) growth.…”

Section: Introductionmentioning

confidence: 99%

“…We have recently demonstrated that addition of a relatively specific inhibitor of TLK, thioridazine (THD) ( Ronald et al., 2013 ), which we repurposed for the blockage of the axis, results in fact in apoptosis of LNCaP and TRAMP-C2 cells concomitantly treated with BIC. In addition, it suppresses the late re-growth of PCa in the TRAMP mouse following castration ( Singh et al., 2019a , 2019b ). However, THD is a known anti-psychotic and has undesirable side effects.…”

Section: Introductionmentioning

confidence: 99%

Generation of Phenothiazine with Potent Anti-TLK1 Activity for Prostate Cancer Therapy

et al. 2020

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Summary Through in vitro kinase assays and docking studies, we report the synthesis and biological evaluation of a phenothiazine analog J54 with potent TLK1 inhibitory activity for prostate cancer (PCa) therapy. Most PCa deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa. Treatments that can suppress the conversion to mCRPC have high potential to be rapidly implemented in the clinics. ADT results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DNA damage response that typically results in temporary cell-cycle arrest of androgen-responsive PCa cells, whereas its abrogation leads to apoptosis. We studied J54 as a potent inhibitor of this axis and as a mediator of apoptosis in vitro and in LNCaP xenografts, which has potential for clinical investigation in combination with ADT. J54 has low affinity for the dopamine receptor in modeling and competition studies and weak detrimental behavioral effects in mice and C. elegans.

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“…Identification of such compounds could therefore become very useful for the treatment of various cancers in combination with selective DNA damaging agents. In particular, we have recently reported that in several models of androgendependent PCa cells, ADT often promotes a cell cycle arrest due to activation of the DDR, and that suppression of the TLK1/Nek1 axis then promotes apoptosis [15,24]. Therefore, there is a prima faciae urgency to identify some novel inhibitors of TLK1 for the adjuvant treatment of PCa.…”

Section: Discussionmentioning

confidence: 99%