Kinesin Family Member C1 (KIFC1) Accelerates Proliferation and Invasion of Endometrial Cancer Cells Through Modulating the PI3K/AKT Signaling Pathway

Kening, Zhou; Zhao, Jian; Qi, Lifang; He, Yingying; Xu, Jiacheng; Dai, Mimi

doi:10.1177/1533033820964217

Cited by 11 publications

(10 citation statements)

References 39 publications

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“…Multiple kinesins also promote the proliferation and progression of pancreatic cancer, 14 hepatocellular carcinoma, 15–17 glioblastoma, 18,19 melanoma, 20,21 and lung adenocarcinoma 22 . KIFC1 and KIF2C are upregulated in EC and accelerate EC cell proliferation 23,24 . Nonetheless, the role of kinesins in EC has not yet been fully investigated.…”

Section: Introductionmentioning

confidence: 99%

“…Multiple kinesins also promote the proliferation and progression of pancreatic cancer[14], hepatocellular carcinoma [15][16][17], glioblastoma [18,19], melanoma [20,21], and lung adenocarcinoma [22]. KIFC1 and KIF2C are upregulated and accelerate the proliferation of EC [23,24]. However, the role of kinesins in EC has not yet been fully investigated.In the present study, to evaluate the role of kinesins in EC, we analyzed differentially expressed kinesins in The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) and GSE17025 databases and found that kinesin family member 4A (KIF4A) was most prominently upregulated.…”

mentioning

confidence: 99%

“…22 KIFC1 and KIF2C are upregulated in EC and accelerate EC cell proliferation. 23,24 Nonetheless, the role of kinesins in EC has not yet been fully investigated.…”

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confidence: 99%

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KIF4A promotes genomic stability and progression of endometrial cancer through regulation of TPX2 protein degradation

Zhang

Zhao

et al. 2022

Molecular Carcinogenesis

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BackgroundKinesin family member 4A (KIF4A) belongs to the kinesin superfamily proteins, which are closely associated with mitophagy. However, the role of KIF4A in endometrial cancer (EC) remains poorly characterized. Here, we aimed to explore the function and regulatory mechanisms of KIF4A in EC. MethodsThe expression of KIF4A was evaluated by quantitative polymerase chain reaction, western blotting, and immunohistochemistry. Cell proliferation was measured using Cell Counting Kit-8, clone formation, and 5ethynyl-2′-deoxyuridine staining assays. Flow cytometry was performed using annexin V/propidium iodide (PI) to identify apoptotic cells and PI staining to analyze the cell cycle. RNA-seq, coimmunoprecipitation, immuno uorescence, and western blotting were performed to explore the underlying mechanism. ResultsIn this study, we demonstrated that KIF4A was upregulated and predicted a poor prognosis in patients with EC. KIF4A knockdown in EC cells resulted in attenuated proliferative capacity and promoted cell cycle arrest and apoptosis induced by increased DNA damage. Mechanistic investigations indicated that KIF4A knockdown exacerbated DNA damage repair and response by regulating the stability of the spindle assembly factor TPX2. ConclusionsKIF4A promotes genomic stability and progression of endometrial cancer through regulation of TPX2 protein degradation. KIF4A may serve as a promising therapeutic target for endometrial cancer molecular mechanism of EC progression and identify novel diagnostic markers and therapeutic targets for patients with EC. Kinesins are microtubule-based motor proteins that mediate diverse functions within the cell, including the transport of vesicles, organelles, chromosomes, and protein complexes and the movement of microtubules [8,9]. Individual kinesin family members have speci c functions. Some kinesins are involved in axonal transport, whereas others function exclusively during mitosis [10]. To date, 45 kinesin superfamily proteins (KIFs) with varying functions have been discovered in humans [11], and at least 12 of them are required in various aspects of mitosis, including bipolar spindle assembly, chromosome alignment, chromosome segregation, and cytokinesis [12,13]. Multiple kinesins also promote the proliferation and progression of pancreatic cancer[14], hepatocellular carcinoma [15][16][17], glioblastoma [18,19], melanoma [20,21], and lung adenocarcinoma [22]. KIFC1 and KIF2C are upregulated and accelerate the proliferation of EC [23,24]. However, the role of kinesins in EC has not yet been fully investigated.In the present study, to evaluate the role of kinesins in EC, we analyzed differentially expressed kinesins in The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) and GSE17025 databases and found that kinesin family member 4A (KIF4A) was most prominently upregulated. Furthermore, we demonstrated that KIF4A accelerated EC progression by regulating cell proliferation and division by inhibiting the apoptosis of EC cells. Mechanistic investigations demonstr...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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KIF4A promotes genomic stability and progression of endometrial cancer through regulation of TPX2 protein degradation

Zhang

Zhao

et al. 2022

Molecular Carcinogenesis

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“…The clustering of extra centrosomes into two functional spindle poles is modulated by a group of proteins called the kinesin‐14 family (K‐14F) ubiquitous to all eukaryotes 9 . Kinesin family member C1 (KIFC1), C2 (KIFC2) and C3 (KIFC3), three microtubule motor proteins of K‐14F deciphered so far in humans, plays a substantial role in microtubule‐dependent targeted transport of cellular consignments, spindle pole organization, chromosome segregation, spermatogenesis and oocyte development 10–12 …”

Section: Introductionmentioning

confidence: 99%

“…9 Kinesin family member C1 (KIFC1), C2 (KIFC2) and C3 (KIFC3), three microtubule motor proteins of K-14F deciphered so far in humans, plays a substantial role in microtubule-dependent targeted transport of cellular consignments, spindle pole organization, chromosome segregation, spermatogenesis and oocyte development. [10][11][12] Akin to the KIFC1, Ncd in the fruit fly and XCTK2 in the African clawed toad are also well-studied kinesins of the K-14F. 13 Like other members of K-14F, KIFC1 structurally consists of three functional domains: the N-terminal tail domain, central superhelical stalk and the C-terminal motor domain.…”

Section: Introductionmentioning

confidence: 99%

Target‐based virtual screening, computational multiscoring docking and molecular dynamics simulation of small molecules as promising drug candidate affecting kinesin‐like protein KIFC1

Khan

Ahmad

Rabbani³

et al. 2022

Cell Biochemistry & Function

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The kinesin family member C1 (KIFC1) is an essential protein that facilitates the bipolar division of neoplastic cells. Inhibiting KIFC1 by small molecules is a lucrative strategy to impede bipolar mitosis leading to the apoptosis of cancerous cells. The research aims to envisage small‐molecule inhibitors targeting KIFC1. The Mcule database, a comprehensive online digital platform containing more than five million chemical compounds, was used for structure‐based virtual screening (SBVS). Druglikeness filtration sifted 2,293,282 chemical hits that further narrowed down to 49 molecules after toxicity profiling. Finally, 39 compounds that comply with the BOILED‐Egg permeation predictive model of the ADME rules were carried forward for multiscoring docking using the AutoDock Vina inbuilt to Mcule drug discovery platform, DockThor and SwissDock tools. The mean of ΔG terms produced by docking tools was computed to find consensus top ligand hits. AZ82 exhibited stronger binding (Consensus ΔG: −7.99 kcal mol−1) with KIFC1 among reference inhibitors, for example, CW069 (−7.57 kcal mol−1) and SR31527 (−7.01 kcal mol−1). Ten ligand hits namely, Mcule‐4895338547 (Consensus ΔG: −8.69 kcal mol−1), Mcule‐7035674888 (−8.42 kcal mol−1), Mcule‐5531166845 (−8.53 kcal mol−1), Mcule‐3248415882 (−8.55 kcal mol−1), Mcule‐291881733 (−8.41 kcal mol−1), Mcule‐5918624394 (−8.44), Mcule‐3470115427 (−8.47), Mcule‐3686193135 (−8.18 kcal mol−1), Mcule‐3955355291 (8.09 kcal mol−1) and Mcule‐9534899193 (−8.01 kcal mol−1) depicted strong binding interactions with KIFC1 in comparison to potential reference inhibitor AZ82. The top four ligands and AZ82 were considered for molecular dynamics simulation of 50 ns duration. Toxicity profiling, physicochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, SASA, ΔGsolv and Rg analyses forecast the ligand mcule‐4895338547 as a promising inhibitor of KIFC1.

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Computational benchmarking of putative KIFC1 inhibitors

Sharma

Setiawan

Hamelberg

et al. 2022

Medicinal Research Reviews

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The centrosome in animal cells is instrumental in spindle pole formation, nucleation, proper alignment of microtubules during cell division, and distribution of chromosomes in each daughter cell. Centrosome amplification involving structural and numerical abnormalities in the centrosome can cause chromosomal instability and dysregulation of the cell cycle, leading to cancer development and metastasis. However, disturbances caused by centrosome amplification can also limit cancer cell survival by activating mitotic checkpoints and promoting mitotic catastrophe. As a smart escape, cancer cells cluster their surplus of centrosomes into pseudo‐bipolar spindles and progress through the cell cycle. This phenomenon, known as centrosome clustering (CC), involves many proteins and has garnered considerable attention as a specific cancer cell‐targeting weapon. The kinesin‐14 motor protein KIFC1 is a minus end‐directed motor protein that is involved in CC. Because KIFC1 is upregulated in various cancers and modulates oncogenic signaling cascades, it has emerged as a potential chemotherapeutic target. Many molecules have been identified as KIFC1 inhibitors because of their centrosome declustering activity in cancer cells. Despite the ever‐increasing literature in this field, there have been few efforts to review the progress. The current review aims to collate and present an in‐depth analysis of known KIFC1 inhibitors and their biological activities. Additionally, we present computational docking data of putative KIFC1 inhibitors with their binding sites and binding affinities. This first‐of‐kind comparative analysis involving experimental biology, chemistry, and computational docking of different KIFC1 inhibitors may help guide decision‐making in the selection and design of potent inhibitors.

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Kinesin Family Member C1 (KIFC1) Accelerates Proliferation and Invasion of Endometrial Cancer Cells Through Modulating the PI3K/AKT Signaling Pathway

Cited by 11 publications

References 39 publications

KIF4A promotes genomic stability and progression of endometrial cancer through regulation of TPX2 protein degradation

KIF4A promotes genomic stability and progression of endometrial cancer through regulation of TPX2 protein degradation

Target‐based virtual screening, computational multiscoring docking and molecular dynamics simulation of small molecules as promising drug candidate affecting kinesin‐like protein KIFC1

Computational benchmarking of putative KIFC1 inhibitors

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