Cell cycle regulation and anticancer drug discovery

Cellular growth,development,and differentiation are tightly controlled by a conserved biological mechanism:the cell cycle.This cycle is primarily regulated by cyclin-dependent kinase(CDK)-cyclin complexes,checkpoint kinases,and CDK inhibitors.Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells.Given its importance in tumorigenesis,several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as singleagent therapy and in combination with traditional cytotoxic or molecular targeting agents.In this review,we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development,including both pan-CDK inhibitors and CDK4/6-selective inhibitors.In addition,we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.

Viral infections and cell cycle G2/M regulation

Progression of cells from G2 phase of the cell cycle to mitosis is a tightly regulated cellular process that requires activation of the Cdc2 kinase, which determines onset of mitosis in all eukaryotic cells. In both human and fission yeast (Schizosaccharomyces pombe) cells, the activity of Cdc2 is regulated in part by the phosphorylation status of tyrosine 15 (Tyr15) on Cdc2, which is phosphorylated by Wee1 kinase during late G2 and is rapidly dephosphorylated by the Cdc25 tyrosine phosphatase to trigger entry into mitosis. These Cdc2 regulators are the downstream targets of two well- characterized G2/M checkpoint pathways which prevent cells from entering mitosis when cellular DNA is damaged or when DNA replication is inhibited. Increasing evidence suggests that Cdc2 is also commonly targeted by viral proteins, which modulate host cell cycle machinery to benefit viral survival or replication. In this review, we describe the effect of viral protein R (Vpr) encoded by human immunodeficiency virus type 1 (HIV-1) on cell cycle G2/M regulation. Based on our current knowledge about this viral effect, we hypothesize that Vpr induces cell cycle G2 arrest through a mechanism that is to some extent different from the classic G2/M checkpoints. One the unique features distinguishing Vpr-induced G2 arrest from the classic checkpoints is the role of phosphatase 2A (PP2A) in Vpr-induced G2 arrest. Interestingly, PP2A is targeted by a number of other viral proteins including SV40 small T antigen, polyomavirus T antigen, HTLV Tax and adenovirus E4orf4. Thus an in-depth understanding of the molecular mechanisms underlying Vpr-induced G2 arrest will provide additional insights into the basic biology of cell cycle G2/M regulation and into the biological significance of this effect during host-pathogen interactions.

Differential regulation of survivin by p53 contributes to cell cycle dependent apoptosis

Recent studies indicate that cell-cycle checkpoints are tightly correlated with the regulation of apoptosis, in which p53 plays an important role. Our present works show that the expression of E6/E7 oncogenes of human papillomavirus in HeLa cells is inhibited in the presence of anti-tumor reagent tripchlorolide (TC), which results in the up-regulation of p53 in HeLa cells. Interestingly, under the same TC-treatment, the cells at the early S-phase are more susceptible to apoptosis than those at the middle S-phase although p53 protein is stabilized to the same level in both situations. Significant difference is exhibited between the two specified expression profiles. Further analysis demonstrates that anti-apoptotic gene survivin is up-regulated by p53 in the TC-treated middle-S cells, whereas it is down-regulated by p53 in the TC-treated early-S cells. Taken together, the present study indicates that the differential p53-regulated expres- sion of survivin at different stages of the cell cycle results in different cellular outputs under the same apoptosis-inducer.

Effect of Exogenous p16ink4a and hRb1 Genes on Cell Cycle Regulation of Osteosarcoma Cell

To study the effect on regulation of cell cycle of osteosarcoma cell line MG63 tranceduced with exogenous p16ink4a and hRbl genes, pIRES-p16ink4a-hRb1, pIRES-p16ink4a and pIREShRbl plasmids were constructed by gene recombination technology. The recombinant plasmid was transferred into osteosarcoma cell line MG63 by metafectene, and the resistant clones were selected by G418 selective medium, mRNA and protein expression of osteosarcoma cell line were assayed by RT-PCR and Western-Blot respectively. Cell cycle and apoptosis were analyzed by subG1 flow cytometric. Cell proliferation was tested by MTT. In the genome of these transfected target cells, the expression of p16ink4a and hRb1 mRNA and protein were detected respectively in vitro. It was demonstrated with subG1 flow cytometric analysis and MTT method that p16ink4a and hRbl genes cooperation more significantly inhibited cell growth and induced a more marked G1 arrest and apoptosis than p16ink4a/hRb1 alone （P〈0.01）. Coexpression of exogenous p16ink4a with hRbl broke the regulatory feedback loop of p16ink4a-cyclinD1/CDK-hRbl and played a more significant role in inhibiting cell growth as well as inducing cell apoptosis than p16ink4a or hRbl did alone in vitro.

Effect of androgen withdrawal on activation of ERKs and expression of cell cycle regulation molecules in human prostate carcinoma cells

Objective: To explore the possible mechanisms of growth regression of human androgen dependent prostate carcinoma cells caused by androgen withdrawal. Methods: After 24 h of treatment with 1 × 10-9 mol/L dihydrotestosterone (DHT), the expression of phosphorylated ERK proteins and cell cycle regulation molecules including CDK2, CDK4, CDK6 and P27kip1 in human androgen dependent prostate carcinoma cell line LNCaP was measured by Western blot analysis 0 h, 8 h and 24 h of after androgen withdrawal. Human androgen independent prostate carcinoma cell line PC-3 was also examined as control. Results: Down-regulation of phosphorylated ERK, CDK2, CDK4 and CDK6 and up-regulation of P27kip1 were found initially in LNCaP cell line 8 h after androgen withdrawal. The levels of phosphorylated ERK and CDKs decreased continuously and reached the lowest after 24 h, while continuous elevation of P27kip1 was detected thereafter to 24 h. No expression change of phosphorylated ERK, CDKs and P27kip1 were detected in PC-3 cell line. Conclusion: The androgen withdrawal can cause ERKs activation decrease and cell cycle regulation molecules changes, which may be one of the mechanisms for inhibited growth of androgen dependent prostate carcinoma after androgen ablation by either operative or medicine methods.

Cell cycle regulation through primary cilium:A long-forgotten story

Protruded from cytomembrane,primary cilium is a widespread cell organelle that can be found in almost all cell types in Mammalia.Because of its comprehensive requirement in various cellular activities and various functions in different organs,primary cilium has been a valuable research area of human pathology research since the turn of the millennium.And the potential application of the interaction between primary cilia and cell cycle regulation may be the most promising direction as many primary cilium-caused diseases are found to be caused by cell cycle dysregulation resulted from primary cilia defects.Therefore,a deep understanding of the interaction between primary cilia and the cell cycle is in great need.Hence in this review,we mainly described how the interaction between primary cilia and cell cycle proceeds and demonstrated three hypotheses raised from much different research.These hypotheses include(1)Primary cilium as a cellular signaling hub to regulate the cell cycle,(2)Primary cilium as a reservoir of cell cycle regulation-related factors,and(3)Primary cilium as a cell cycle checkpoint or a brake.Nonetheless,we also call for more attention on research of interaction between cell cycle and primary cilia and tried to point out some possible research directions for those who are interested.

Anti-cancer activity of Tonglian decoction against esophageal cancer cell proliferation through regulation of the cell cycle and PI3K/Akt signaling pathway

Objective:The purpose of this study was to observe the anti-cancer activity of Tonglian decoction(TD)on esophageal cancer(EC)cells in vitro,and to elucidate the related molecular mechanisms in the cell cycle and PI3K/Akt signaling pathway.Methods:EC9706 cells were cultured in RPMI 1640 medium supplemented with 10%calf serum at 37
C in a 5%CO2 incubator.The cells were treated with rat serum containing TD or the serum of rats administered Xiaoaiping as a positive control drug.Cell proliferation was assessed by methylthiazolyldiphenyl-tetrazolium bromide assays.Cell morphology was observed under a microscope.The cell cycle was examined by flow cytometry.Protein expression in the PI3K/Akt signaling pathway was measured by western blotting.Results:TD mainly inhibited cell proliferation.Concentrations of 50%cell inhibition by rat serum containing TD or Xiaoaiping were 73.6 and 153.8 mL/mL,respectively.TD also influenced cell morphology characterized by small shrunken cells.Cell colonies became small and the cell proliferation rate was slower.In cell cycle analysis,the percentage of cells in S phase was decreased significantly by TD and Xiaoaiping compared with the blank control group(P<.05).Western blotting showed that serum containing TD strongly downregulated EGFR,PI3K,Akt,p-Akt,and mTOR expression compared with the blank control group(P<.05).Conclusion:TD could inhibit EC9706 carcinoma cell proliferation by blocking the cell cycle progression in S phase.The possible mechanism was inhibition of multiple targets in the PI3K/Akt signaling pathway by TD.

Morphological adaptation of sheep's rumen epithelium to high-grain diet entails alteration in the expression of genes involved in cell cycle regulation, cell proliferation and apoptosis

Background: The objectives of this study were to characterize changes in the relative m RNA expression of candidate genes and proteins involved in cell cycle regulation, cell proliferation and apoptosis in the ruminal epithelium(RE) of sheep during high-grain(HG) diet adaptation.Results: Twenty sheep were assigned to four groups with five animals each. These animals were assigned to different periods of HG diet(containing 40% forage and 60% concentrate mix) feeding. The HG groups received an HG diet for7(G7, n = 5), 14(G14, n = 5) and 28 d(G28, n = 5), respectively. In contrast, the control group(CON, n = 5) was fed the forage-based diet for 28 d. The results showed that HG feeding linearly decreased(P < 0.001) the ruminal p H, and increased the concentrations of ruminal total volatile fatty acid(linear, P = 0.001), butyrate(linear, P < 0.001), valerate(quadratic P = 0.029) and the level of IGF-1(quadratic, P = 0.043) in plasma. The length(quadratic, P = 0.004), width(cubic, P = 0.015) and surface of the ruminal papillae(linear, P = 0.003) were all enlarged after 14 d of HG diet feeding.HG feeding cubically increased the number of cell layers forming the stratum corneum(SC, P < 0.001) and the thickness of the SC(P < 0.001) and stratum basale(P < 0.001). The proportion of basal layer cells in the RE decreased(linear, P < 0.001) in the G0/G1-phase, but it increased linearly(P = 0.006) in the S-phase and cubically(P = 0.004) in the G2/M-phases. The proportion of apoptosis cells in G7, G14 and G28 was reduced compared to the CON(quadratic, P <0.001). HG diet feeding linearly decreased the m RNA expression of Cyclin E1(P = 0.021) and CDK-2(P = 0.001) and(P = 0.027) the protein expression of Cyclin E1. Feeding an HG diet linearly increased the m RNA expression of genes IGFBP-2(P = 0.034) and IGFBP 5(P < 0.009), while linearly decreasing(P < 0.001) the IGFBP 3 expression. The expression of cell apoptosis gene Caspase 8 decreased(quadratic, P = 0.012), while Bad m RNA expression tended to decrease(cubic, P = 0.053) after HG feeding.Conclusions: These results demonstrated sequential changes in rumen papillae size, cell cycle regulation and the genes involved in proliferation and apoptosis as time elapsed in feeding a high-grain diet to sheep.

CtrA Is Nonessential for Cell Cycle Regulation in <i>Rhodobacter sphaeroides</i>

The bacterial cell cycle consists of a series of genetically coordinated biochemical and biophysical events. In Caulobacter crescentus, CtrA is an essential cell cycle regulator that modulates many cell cycle processes. In the present study, the role of the CtrA was investigated in Rhodobacter sphaeroides 2.4.1 by employing genetic, molecular, and bioinformatic approaches. Examination of the ctrA-null mutant revealed that the loss of CtrA did not affect growth characteristics and cell morphology in R. sphaeroides when grown under aerobic or photosynthetic growth conditions but slower growth was noticed in the anaerobic-dark-DMSO condition. Phylogenetic analyses demonstrated that CtrA has diversified its role in major lineages of α-Proteobacteria and has possibly been involved in adaptation to variable lifestyles. Analysis of the CtrA binding sites in the R. sphaeroides genome suggests that CtrA may regulate 127 genes involving different cellular processes. Protein homology searches revealed that only a small number of ctrA-regulated genes are homologous across C. crescentus, R. capsulatus, and R. sphaeroides. Comparison of the functions of putative ctrA-regulated genes in C. crescentus, R. capsulatus, and R. sphaeroides revealed that all three species possessed broad pathway control across a variety of cluster of orthologous gene functions (COGs). However, interestingly, it seems that the essentiality of CtrA in C. crescentus may depend more on the selective control that it exerts on a few critical cell cycle genes and pathways that are not controlled by CtrA in a similar fashion in R. capsulatus and R. sphaeroides.

Cell cycle dependent regulation of gap junction coupling and apoptosis in GFSHR-17 granulosa cells

Recent results have shown that the level of gap junction coupling could modulate the induction of apoptotic reactions. We previously observed that 1H-[1,2, 4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ), a block- er of guanylyl cyclase, inhibited gap junction coupling and thereby promoted activation of characteristic apoptotic reactions such as chromatin condensation, DNA strand breaking, and formation of blebs in GFSHR-17 granulosa cells, the in vitro model for granulosa cells of the maturing ovular follicle. In the present report, we focus on the effects of ODQ with respect to the cell cycle in GFSHR-17 granulosa cells. In synchronised GFSHR-17 granulosa cells, the double whole-cell patch-clamp technique revealed that gap junction conductance in mitotic cells was reduced in comparison to cells in interphase. This reduction of gap junction conductance correlated with a reduction of non-phosphorylated Cx43 in mitotic cells. We compared the stimulation of apoptotic reactions by ODQ between cells in mitosis and in interphase. We observed that the induction of both chromatin condensation and DNA strand breaking by ODQ was increased in mitotic cells, as compared to cells in interphase. The effects of ODQ were not observed in He-La cells that do not express connexins. The results in- dicate that reduction of gap junction coupling in mitotic GFSHR-17 granulosa cells depends on phosphor- rylation of Cx43 and raises the sensitivity to stimulation of apoptosis. We propose that gap junction coupling is involved in regulation of apoptosis of granulosa cells in maturing ovular follicle.

Down-regulation of Hsp90 could change cell cycle distribution and increase drug sensitivity of tumor cells

AIM:To construct Hsp90 antisense RNA eukaryotic expression vector, transfect it into SGC7901 and SGC7901/VCR of MDR-type human gastric cancer cell lines, HCC7402 of human hepatic cancer and Ec109 of human esophageal cancer cell lines, and to study the cell cycle distribution of the gene transected cells and their response to chemotherapeutic drugs.METHODS:A 1.03kb cDNA sequence of Hsp90beta was obtained from the primary plasmid phHSP90 by EcoR I and BamH I nuclease digestion and was cloned to the EcoR I and BamH I site of the pcDNA by T4DNA ligase and an antisense orientation of Hsp90beta expression vector was constructed. The constructs were transfected with lipofectamine and positive clones were selected with G418. The expression of RNA was determined with dot blotting and RNase protection assay, and the expression of Hsp90 protein determined with western blot. Cell cycle distribution of the transfectants was analyzed with flow cytometry, and the drug sensitivity of the transfectants to Adriamycin (ADR), vincrinstine (VCR), mitomycin (MMC) and cyclophosphamide (CTX) with MTT and intracellular drug concentration of the transfectants was determined with flow cytometry.RESULTS:In EcoR I and BamH I restriction analysis, the size and the direction of the cloned sequence of Hsp90beta remained what had been designed and the gene constructs were named pcDNA-Hsp90.AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 cell clones all expressed Hsp90 anti-sense RNA. The expression of Hsp90 was down-regulated in AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 cell clones. Cell cycle distribution was changed differently. In AH-SGC7901/VCR and AH-Ec109 cells, G(1) phase cells were increased; S phase and G(2) phase cells were decreased as compared with their parental cell lines. In AH-SGC7901 cell, G(1)phase cells were decreased, G(2) phase cells increased and S phase cells were not changed, and in AH-HCC7402 cells G(1), S and G(2) phase cells remained unchanged as compared with their parental cell lines. The sensitivity of AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 to chemotherapeutic drugs, the sensitivity of AH-SGC7901/VCR to ADR, VCR, MMC and CTX the sensitivity of AH-HCC7402 to ADR and VCR, and the sensitivity of Ec109 to ADR, VCR and CTX all increased as compared with their parental cell lines. The mean fluorescence intensity of ADR in AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 was also significantly elevated (P 【 0.05).CONCLUSION: Down-regulation of Hsp90 could change cell cycle distribution and increase the drug sensitivity of tumor cells.

Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma

MicroRNAs are short regulatory RNAs that negatively modulate gene expression at the post-transcriptional level, and are deeply involved in the pathogenesis of several types of cancers. To investigate whether specific miRNAs and their target genes participate in the molecular pathogenesis of laryngeal carcinoma, oligonucleotide microarrays were used to assess the differential expression profiles of microRNAs and mRNAs in laryngeal carcinoma tissues compared with normal tissues. The oncogeuic miRNA, microRNA-21 （miR-21）, was found to he npregulated in laryngeal carcinoma tissues. Knockdown of miR-21 by specific antisense oligonucleotides inhibited the proliferation potential of HEp-2 cells, whereas overexpression of miR-21 elevated growth activity of the cells, as detected by the colony formation assay. The cell number reduction caused by miR-21 inhibition was due to the loss of control of the G1-S phase transition, instead of a noticeable increase in apoptosis. Subsequently, a new target gene of miR- 21, BTG2, was found to be downregulated in laryngeal carcinoma tissues. BTG2 is known to act as a pan-cell cycle regulator and tumor suppressor. These findings indicate that aberrant expression of miR-21 may contribute to the malignant phenotype of laryngeal carcinoma by maintaining a low level of BTG2. The identification of the oneogenic miR-21 and its target gene, BTG2, in laryngeal carcinoma is potentially valuable for cancer diagnosis and therapy.

Regulation of the G1 phase of the mammalian cell cycle

In any multi-cellular organism, the balance between cell division and cell death maintains a constant cell number. Both cell division cycle and cell death are highly regulated events. Whether the cell will proceed through the cycle or not, depends upon whether the conditions required at the checkpoints during the cycle are fulfilled. In higher eucaryotic cells, such as mammalian cells, signals that arrest the cycle usually act at a G1 checkpoint. Cells that pass this restriction point are committed to complete the cycle. Regulation of the GI phase of the cell cycle is extremely complex and involves many different families of proteins such as retinoblastoma family cyclin dependent kinases, cyclins, and cyclic kinase inhibitors.

Downregulation of SNRPG induces cell cycle arrest and sensitizes human glioblastoma cells to temozolomide by targeting Myc through a p53-dependent signaling pathway

Objective:Temozolomide(TMZ)is commonly used for glioblastoma multiforme(GBM)chemotherapy.However,drug resistance limits its therapeutic effect in GBM treatment.RNA-binding proteins(RBPs)have vital roles in posttranscriptional events.While disturbance of RBP-RNA network activity is potentially associated with cancer development,the precise mechanisms are not fully known.The SNRPG gene,encoding small nuclear ribonucleoprotein polypeptide G,was recently found to be related to cancer incidence,but its exact function has yet to be elucidated.Methods:SNRPG knockdown was achieved via short hairpin RNAs.Gene expression profiling and Western blot analyses were used to identify potential glioma cell growth signaling pathways affected by SNRPG.Xenograft tumors were examined to determine the carcinogenic effects of SNRPG on glioma tissues.Results:The SNRPG-mediated inhibitory effect on glioma cells might be due to the targeted prevention of Myc and p53.In addition,the effects of SNRPG loss on p53 levels and cell cycle progression were found to be Myc-dependent.Furthermore,SNRPG was increased in TMZ-resistant GBM cells,and downregulation of SNRPG potentially sensitized resistant cells to TMZ,suggesting that SNRPG deficiency decreases the chemoresistance of GBM cells to TMZ via the p53 signaling pathway.Our data confirmed that SNRPG suppression sensitizes GBM cells to TMZ by targeting Myc via the p53 signaling cascade.Conclusions:These results indicated that SNRPG is a probable molecular target of GBM and suggested that suppressing SNRPG in resistant GBM cells might be a substantially beneficial method for overcoming essential drug resistance.

NCAPD2 serves as a potential prognostic biomarker for lung adenocarcinoma and promotes cell proliferation,migration,invasion and cell cycle in vitro

Objectives:The pro-oncogenic effects of NCAPD2 have been extensively studied across various tumor types;however,its precise role within the context of lung adenocarcinoma(LUAD)remains elusive.This study aims to elucidate the biological functions of NCAPD2 in LUAD and unravel the underlying mechanistic pathways.Methods:Utilizing bioinformatics methodologies,we explored the differential expression of NCAPD2 between normal and tumor samples,along with its correlations with clinical-pathological characteristics,survival prognosis,and immune infiltration.Results:In the TCGA-LUAD dataset,tumor samples demonstrated significantly elevated levels of NCAPD2 expression compared to normal samples(p<0.001).Clinically,higher NCAPD2 expression was notably associated with advanced T,N,and M stages,pathologic stage,gender,smoking status,and diminished overall survival(OS).Moreover,differentially expressed genes(DEGs)associated with NCAPD2 were predominantly enriched in pathways related to cell division.Immune infiltration analysis revealed that NCAPD2 expression levels were linked to the infiltration of memory B cells,naïve CD4+T cells,activated memory CD4+T cells,and M1 macrophages.In vitro experiments demonstrated that silencing NCAPD2 suppressed LUAD cell proliferation,migration,invasion,epithelial-mesenchymal transition(EMT),and cell cycle progression.Conclusions:In summary,NCAPD2 may represent a promising prognostic biomarker and novel therapeutic target for LUAD.

Hydrangea serrata extract exerts tumor inhibitory activity against hepatocellular carcinoma HepG2 cells via inducing p27/CDK2-mediated cell cycle arrest and apoptosis

Objective:To examine the inhibitory effect of Hydrangea serrata extract against hepatocellular carcinoma HepG2 cells and its underlying mechanisms.Methods:The effects of Hydrangea serrata extract on growth inhibition of tumor cells and spheroids were assessed using MTT and 3D culture assays.Quantitative real-time PCR and Western blot analyses were employed to investigate the changes in mRNA and protein expression levels of molecules related to cell cycle and apoptosis.Results:Hydrangea serrata extract effectively inhibited the growth of both tumor cells and spheroids.The extract also significantly upregulated p27 mRNA expression and downregulated CDK2 mRNA expression,leading to cell cycle arrest.Moreover,increased BAX/Bcl-2 ratio as well as caspase-9 and-3 were observed after treatment with Hydrangea serrata extract,indicating the induction of tumor cell apoptosis.Conclusions:Hydrangea serrata extract has the potential to alleviate tumors by effectively modulating cell-cycle-related gene expressions and inducing apoptosis,thereby inhibiting tumor growth.

Antitumor Effect of Apcin on Endometrial Carcinoma via p21-Mediated Cell Cycle Arrest and Apoptosis

Objective Endometrial carcinoma(EC)is a prevalent gynecological malignancy characterized by increasing incidence and mortality rates.This underscores the critical need for novel therapeutic targets.One such potential target is cell division cycle 20(CDC20),which has been implicated in oncogenesis.This study investigated the effect of the CDC20 inhibitor Apcin on EC and elucidated the underlying mechanism involved.Methods The effects of Apcin on EC cell proliferation,apoptosis,and the cell cycle were evaluated using CCK8 assays and flow cytometry.RNA sequencing(RNA-seq)was subsequently conducted to explore the underlying molecular mechanism,and Western blotting and coimmunoprecipitation were subsequently performed to validate the results.Animal studies were performed to evaluate the antitumor effects in vivo.Bioinformatics analysis was also conducted to identify CDC20 as a potential therapeutic target in EC.Results Treatment with Apcin inhibited proliferation and induced apoptosis in EC cells,resulting in cell cycle arrest.Pathways associated with apoptosis and the cell cycle were activated following treatment with Apcin.Notably,Apcin treatment led to the upregulation of the cell cycle regulator p21,which was verified to interact with CDC20 and consequently decrease the expression of downstream cyclins in EC cells.In vivo experiments confirmed that Apcin treatment significantly impeded tumor growth.Higher CDC20 expression was observed in EC tissue than in nonmalignant tissue,and increased CDC20 expression in EC patients was associated with shorter overall survival and progress free interval.Conclusion CDC20 is a novel molecular target in EC,and Apcin could be developed as a candidate antitumor drug for EC treatment.

Krill oil ameliorates benign prostatic hyperplasia by regulating G1-phase cell cycle arrest and altering signaling pathways and benign prostatic hyperplasia-associated markers

Krill oil(KO)exhibits various biological activities,such as anti-inflammatory and antitumor effects.However,the inhibitory effects of benign prostatic hyperplasia(BPH)in vitro and in vivo have not yet been studied.This study investigated the anti-BPH effects of KO extracted by an enzymatic hydrolysis method.KO treatment inhibited the proliferation of WMPY-1 and BPH-1 cells by induction of G0/G1 phase arrest through the modulation of positive and negative regulators in both prostate cell types.KO treatment stimulated phosphorylation of c-Jun N-terminal kinase(JNK)and p38 signaling.In addition,KO changed the expression of BPH-related markers(5α-reductase,androgen receptor,FGF,Bcl-2,and Bax)and the activity of the proliferation-mediated NF-κB binding motif.KO-induced levels of proliferation-mediated molecules of prostate cells were attenuated in the presence of siRNA-specific p-38(si-p38)and JNK(si-JNK).Furthermore,the administration of KO alleviated prostate size and weight and the cell layer thickness of prostate glands in a testosterone enanthate-induced BPH rat model.KO treatment altered the level of dihydrotestosterone in serum and the expression levels of BPH-related markers in prostate tissues.Finally,KO-mediated inhibition of prostatic growth was validated by histological analysis.These results suggest that KO has an inhibitory effect on BPH in prostate cells in vitro and in vivo.Thus,KO might be a potential prophylactic or therapeutic agent for patients with BPH.

A short overview of the lead iodide residue impact and regulation strategies in perovskite solar cells

Lead iodide(PbI2) is a vital raw material for preparing perovskite solar cells(PSCs),and it not only takes part in forming the light absorption layer but also remains in the grain boundary as a passivator.In other words,the PbI2 content in the precursor and as formed film will affect the efficiency and stability of the PSCs.With moderate residual PbI2,it passivates the bulk/surface defects of perovskite,reduces the interfacial recombination,promotes the perovskite stability,minimizes the device hysteresis,and so on.Deficient PbI2 residue will reduce the interfacial passivation effect and device performance.In addition to facilitating the non-radiative recombination,over PbI2 residue can also lead to electronic insulation in the grain boundary and deteriorate the device performance.However,the impact and regulation of PbI2 residue on the device performance and stability is still not fully understood.Herein,a comprehensive and detailed review is presented by discussing the PbI2 residue impact and its regulation strategies(i.e., elimination,facilitation and conversion of the residue PbI2) to manipulate the PbI2 content,distribution and forms.Finally,we also show future outlooks in this field,with an aim to help further the progression of high-efficiency and stable PSCs.

Induction of apoptosis and G2/M cell cycle arrest by oridonin in human gastric cancer BGC-823 cells

Aim To investigate in vitro apoptosis-induction effects of oridonin on gastric tumor cells BGC-823 and its effects on cell cycle, mitochondrial membrane potential and intracellular Ca^2＋ to shed light on the mode of its anticancer action. Methods The MTT method was used to investigate the inhibitory effect of oridonin on BGC-823 cells. The apoptosis-induction effect was evaluated by confocal laser microscopy and flow cytometry. The change of mitochondrial membrane potential and the increase of intracellular Ca^2＋ were assessed by fluorescence probe rhodamine123 and Fluo 3-AM, respectively, with flow cytometry. The expression of apoptosis and cell cycle related proteins was studied using western blotting. Results Oridonin inhibited BGC-823 cells growth with IC50 of 22.21 p, mol.L^-1. It induced apoptosis in a dose-dependent manner. In addition, it decreased mitochondria membrane potential, increased intracellular Ca^2＋, and activated pro-caspase 3. BGC-823 cells were arrested in G2/M cell cycle phase with lower expression of cyclin A protein. The up-regulation of p53 was observed before apoptosis and cell cycle arrest occurred. Conclusion Oridonin inhibits the proliferation of BGC-823 cells through G2/M cell cycle arrest and apoptosis induction, which is mediated by influx of Ca^2＋, up-regulation of p53, activation of caspase-3, and down-regulation of cyclin A.