Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6

Donato, Marta De; Righino, Benedetta; Filippetti, Flavia; Battaglia, Alessandra; Petrillo, Marco; Pirolli, Davide; Scambia, Giovanni; Rosa, Maria Cristina De; Gallo, Daniela

doi:10.1038/s41598-018-34471-y

Cited by 31 publications

(20 citation statements)

References 60 publications

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“…NEK6 has been proven to be a target of miR-506-3p in RB 18. Growing evidence showed that NEK6 played crucial roles in tumorigenesis 34,35. Here, we determine whether HOXA11-AS can regulate NEK6 expression.…”

Section: Discussionmentioning

confidence: 86%

<p>Long non-coding RNA homeobox A11 antisense RNA (HOXA11-AS) promotes retinoblastoma progression via sponging miR-506-3p</p>

Han¹,

Zuo²,

Han³

et al. 2019

OTT

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Background: Long non-coding RNA homeobox A11 antisense RNA (HOXA11-AS) has been reported to be involved in initiation and development of multiple cancers. However, the detailed biological roles and underlying molecular mechanism of HOXA11-AS remain unclear in retinoblastoma (RB). Herein, the goals of this study were to explore the biological function and the potential mechanism of HOXA11-AS in RB. Materials and methods: The expression of HOXA11-AS in RB tissues and cell lines was detected using real-time PCR (qRT-PCR). Cell proliferation, cycle arrest and apoptosis were measured using a cell counting kit 8 and flow cytometry. The target miRNAs of HOXA11-AS was predicted by Starbase2.0 software and was confirmed using a dual-luciferase reporter assay. Result: We found that HOXA11-AS expression was markedly elevated in RB tissues and cell lines compared to normal retina tissues and human retinal epithelial cells, respectively. Functional analysis showed that knockdown of HOXA11-AS in RB cells significantly suppressed cell proliferation, and induced cell cycle arrest at G1/G0 phase and promoted cell apoptosis. We also found that HOXA11-AS could serve as a competing endogenous RNA (ceRNA) that inhibited miR-506-3p expression, which regulated its downstream target NIMA-related kinase 6 (NEK6) in RB. In addition, miR-506-3p inhibitors partially reversed the effect of HOXA11-AS depletion on proliferation, cycle arrest and apoptosis in RB cells. Conclusion: Taken together, these findings demonstrated that HOXA11-AS could promote RB progression by sponging miR-506-3p, suggesting that HOXA-11-AS might be a potential therapeutic target for RB.

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Section: Discussionmentioning

confidence: 86%

<p>Long non-coding RNA homeobox A11 antisense RNA (HOXA11-AS) promotes retinoblastoma progression via sponging miR-506-3p</p>

Han¹,

Zuo²,

Han³

et al. 2019

OTT

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“…First-line chemotherapy for ovarian cancer, which is usually based on a platinum drug, has little impact on the overall survival of patients. Combination treatment with carboplatin and a taxane leads to a better overall clinical response than anthracyclines in patients with ovarian cancer [ 31 , 32 ]. However, the slight improvement in survival is associated with a significant increase in adverse effects, underscoring the need to identify and design novel therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness

Gralewska

Gajek

Marczak

et al. 2020

IJMS

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Poly (ADP-ribose) polymerase inhibitor (PARPi, olaparib) impairs the repair of DNA single-strand breaks (SSBs), resulting in double-strand breaks (DSBs) that cannot be repaired efficiently in homologous recombination repair (HRR)-deficient cancers such as BRCA1/2-mutant cancers, leading to synthetic lethality. Despite the efficacy of olaparib in the treatment of BRCA1/2 deficient tumors, PARPi resistance is common. We hypothesized that the combination of olaparib with anticancer agents that disrupt HRR by targeting ataxia telangiectasia and Rad3-related protein (ATR) or checkpoint kinase 1 (CHK1) may be an effective strategy to reverse ovarian cancer resistance to olaparib. Here, we evaluated the effect of olaparib, the ATR inhibitor AZD6738, and the CHK1 inhibitor MK8776 alone and in combination on cell survival, colony formation, replication stress response (RSR) protein expression, DNA damage, and apoptotic changes in BRCA2 mutated (PEO-1) and HRR-proficient BRCA wild-type (SKOV-3 and OV-90) cells. Combined treatment caused the accumulation of DNA DSBs. PARP expression was associated with sensitivity to olaparib or inhibitors of RSR. Synergistic effects were weaker when olaparib was combined with CHK1i and occurred regardless of the BRCA2 status of tumor cells. Because PARPi increases the reliance on ATR/CHK1 for genome stability, the combination of PARPi with ATR inhibition suppressed ovarian cancer cell growth independently of the efficacy of HRR. The present results were obtained at sub-lethal doses, suggesting the potential of these inhibitors as monotherapy as well as in combination with olaparib.

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“…De Donato et al (2015) found that NEK6 overexpression decreased cisplatin sensibility in A2780 cells, a human ovarian carcinoma cell line [157]. Another study by De Donato et al (2018) found a compound named compound 8, that binds to NEK6 and NEK1 kinase domains and inhibits their kinase activities, increasing cisplatin sensibility in PEO1 cells, another ovarian cancer cell line [158]. Jeon et al (2010) [159] identified that the ectopic expression of NEK6 in JB6 Cl41 cells phosphorylates S727 of STAT3 (Signal transducer and activator of transcription 3), increasing transcriptional activation activity [159].…”

Section: Nek6mentioning

confidence: 96%

On Broken Ne(c)ks and Broken DNA: The Role of Human NEKs in the DNA Damage Response

Pavan

Oliveira

Dias

et al. 2021

Cells

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NIMA-related kinases, or NEKs, are a family of Ser/Thr protein kinases involved in cell cycle and mitosis, centrosome disjunction, primary cilia functions, and DNA damage responses among other biological functional contexts in vertebrate cells. In human cells, there are 11 members, termed NEK1 to 11, and the research has mainly focused on exploring the more predominant roles of NEKs in mitosis regulation and cell cycle. A possible important role of NEKs in DNA damage response (DDR) first emerged for NEK1, but recent studies for most NEKs showed participation in DDR. A detailed analysis of the protein interactions, phosphorylation events, and studies of functional aspects of NEKs from the literature led us to propose a more general role of NEKs in DDR. In this review, we express that NEK1 is an activator of ataxia telangiectasia and Rad3-related (ATR), and its activation results in cell cycle arrest, guaranteeing DNA repair while activating specific repair pathways such as homology repair (HR) and DNA double-strand break (DSB) repair. For NEK2, 6, 8, 9, and 11, we found a role downstream of ATR and ataxia telangiectasia mutated (ATM) that results in cell cycle arrest, but details of possible activated repair pathways are still being investigated. NEK4 shows a connection to the regulation of the nonhomologous end-joining (NHEJ) repair of DNA DSBs, through recruitment of DNA-PK to DNA damage foci. NEK5 interacts with topoisomerase IIβ, and its knockdown results in the accumulation of damaged DNA. NEK7 has a regulatory role in the detection of oxidative damage to telomeric DNA. Finally, NEK10 has recently been shown to phosphorylate p53 at Y327, promoting cell cycle arrest after exposure to DNA damaging agents. In summary, this review highlights important discoveries of the ever-growing involvement of NEK kinases in the DDR pathways. A better understanding of these roles may open new diagnostic possibilities or pharmaceutical interventions regarding the chemo-sensitizing inhibition of NEKs in various forms of cancer and other diseases.

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Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6

Cited by 31 publications

References 60 publications

<p>Long non-coding RNA homeobox A11 antisense RNA (HOXA11-AS) promotes retinoblastoma progression via sponging miR-506-3p</p>

<p>Long non-coding RNA homeobox A11 antisense RNA (HOXA11-AS) promotes retinoblastoma progression via sponging miR-506-3p</p>

PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness

On Broken Ne(c)ks and Broken DNA: The Role of Human NEKs in the DNA Damage Response

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