scholarly journals The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein Interacts with CDK1 To Induce G2 Cell Cycle Arrest and Positively Regulate Viral Replication

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Sihua Liu ◽  
Hongyun Liu ◽  
Jun Kang ◽  
Leling Xu ◽  
Keke Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Viral Replication ◽  
Cell Cycle Arrest ◽  
Host Cell ◽  
Nuclear Import ◽  
Hemorrhagic Fever ◽  
Cyclin B1 ◽  
Cycle Arrest ◽  
Infected Cells ◽  
Severe Fever

ABSTRACT Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. While many viruses subvert the host cell cycle to promote viral growth, it is unknown whether this is a strategy employed by SFTSV. In this study, we investigated how SFTSV manipulates the cell cycle and the effect of the host cell cycle on SFTSV replication. Our results suggest that cells arrest at the G2/M transition following infection with SFTSV. The accumulation of cells at the G2/M transition did not affect virus adsorption and entry but did facilitate viral replication. In addition, we found that SFTSV NSs, a nonstructural protein that forms viroplasm-like structures in the cytoplasm of infected cells and promotes virulence by modulating the interferon response, induces a large number of cells to arrest at the G2/M transition by interacting with CDK1. The interaction between NSs and CDK1, which is inclusion body dependent, inhibits formation and nuclear import of the cyclin B1-CDK1 complex, thereby leading to cell cycle arrest. Expression of a CDK1 loss-of-function mutant reversed the inhibitive effect of NSs on the cell cycle, suggesting that this protein is a potential antiviral target. Our study provides new insight into the role of a specific viral protein in SFTSV replication, indicating that NSs induces G2/M arrest of SFTSV-infected cells, which promotes viral replication. IMPORTANCE Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne pathogen that causes severe hemorrhagic fever. Although SFTSV poses a serious threat to public health and was recently isolated, its pathogenesis remains unclear. In particular, the relationship between SFTSV infection and the host cell cycle has not been described. Here, we show for the first time that both asynchronized and synchronized SFTSV-susceptible cells arrest at the G2/M checkpoint following SFTSV infection and that the accumulation of cells at this checkpoint facilitates viral replication. We also identify a key mechanism underlying SFTSV-induced G2/M arrest, in which SFTSV NSs interacts with CDK1 to inhibit formation and nuclear import of the cyclin B1-CDK1 complex, thus preventing it from regulating cell cycle progression. Our study highlights the key role that NSs plays in SFTSV-induced G2/M arrest.

scholarly journals Eimeria bovis infections induce G1 cell cycle arrest and a senescence-like phenotype in endothelial host cells

Parasitology ◽  
2020 ◽  
pp. 1-13
Author(s):  
Zahady D. Velásquez ◽  
Sara López-Osorio ◽  
Daniel Waiger ◽  
Carolina Manosalva ◽  
Learta Pervizaj-Oruqaj ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Endothelial Cells ◽  
Cell Cycle Arrest ◽  
Host Cell ◽  
Cyclin B1 ◽  
Host Cells ◽  
Phenotypic Change ◽  
Cyclin E1 ◽  
Cycle Arrest ◽  
Eimeria Bovis

Abstract Apicomplexan parasites are well-known to modulate their host cells at diverse functional levels. As such, apicomplexan-induced alteration of host cellular cell cycle was described and appeared dependent on both, parasite species and host cell type. As a striking evidence of species-specific reactions, we here show that Eimeria bovis drives primary bovine umbilical vein endothelial cells (BUVECs) into a senescence-like phenotype during merogony I. In line with senescence characteristics, E. bovis induces a phenotypic change in host cell nuclei being characterized by nucleolar fusion and heterochromatin-enriched peripheries. By fibrillarin staining we confirm nucleoli sizes to be increased and their number per nucleus to be reduced in E. bovis-infected BUVECs. Additionally, nuclei of E. bovis-infected BUVECs showed enhanced signals for HH3K9me2 as heterochromatin marker thereby indicating an infection-induced change in heterochromatin transition. Furthermore, E. bovis-infected BUVECs show an enhanced β-galactosidase activity, which is a well-known marker of senescence. Referring to cell cycle progression, protein abundance profiles in E. bovis-infected endothelial cells revealed an up-regulation of cyclin E1 thereby indicating a cell cycle arrest at G1/S transition, signifying a senescence key feature. Similarly, abundance of G2 phase-specific cyclin B1 was found to be downregulated at the late phase of macromeront formation. Overall, these data indicate that the slow proliferative intracellular parasite E. bovis drives its host endothelial cells in a senescence-like status. So far, it remains to be elucidated whether this phenomenon indeed reflects an intentionally induced mechanism to profit from host cell-derived energy and metabolites present in a non-dividing cellular status.

scholarly journals Coronavirus PEDV nucleocapsid protein interacts with p53 to induce cell cycle arrest in S-phase and promotes viral replication

2021 ◽  
Author(s):  
Mingjun Su ◽  
Da Shi ◽  
Xiaoxu Xing ◽  
Shanshan Qi ◽  
Dan Yang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Viral Replication ◽  
Cell Cycle Arrest ◽  
Host Cell ◽  
S Phase ◽  
N Protein ◽  
Diarrhea Virus ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
S Phase Arrest

Subversion of the host cell cycle to facilitate viral replication is a common feature of coronavirus infections. Coronavirus nucleocapsid (N) protein could modulate host cell cycle, but the mechanistic details remain largely unknown. Here, we investigated manipulation of porcine epidemic diarrhea virus (PEDV) N protein on cell cycle and its influence on viral replication. Results indicated that PEDV N-induced Vero E6 cell cycle arrest at S-phase, which promoted viral replication ( P < 0.05). S-phase arrest was dependent on N protein nuclear localization signal S 71 NWHFYYLGTGPHADLRYRT 90 and interaction between N protein and p53. In the nucleus, the binding of N protein to p53 maintained consistently high-level expression of p53, which activated p53-DREAM pathway. The key domain of the N protein interacting with p53 was revealed to be S 171 RGNSQNRGNNQGRGASQNRGGNN 194 (N S171-N194 ), in which G 183 RG 185 are core sites. N S171-N194 and G 183 RG 185 were essential for N-induced S-phase arrest. Moreover, small molecular drugs targeting the N S171-N194 domain of PEDV N protein were screened through molecular docking. Hyperoside could antagonize N protein-induced S-phase arrest by interfering with interaction between N protein and p53 and inhibit viral replication ( P < 0.05). The above experiments were also validated in porcine intestinal cells, and resulting data were in line with that of Vero E6 cells. Therefore, these results revealed that PEDV N protein interacted with p53 to activate p53-DREAM pathway, and subsequently induced S-phase arrest to create a favorable environment for virus replication. These findings provided new insight into the PEDV-host interaction and the design of novel antiviral strategies against PEDV.

scholarly journals Influenza A Virus Replication Induces Cell Cycle Arrest in G0/G1 Phase

2010 ◽  
Vol 84 (24) ◽  
pp. 12832-12840 ◽  
Author(s):  
Yuan He ◽  
Ke Xu ◽  
Bjoern Keiner ◽  
Jianfang Zhou ◽  
Volker Czudai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cell Cycle Progression ◽  
Virus Production ◽  
Phase Cell ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Infected Cells

ABSTRACT Many viruses interact with the host cell division cycle to favor their own growth. In this study, we examined the ability of influenza A virus to manipulate cell cycle progression. Our results show that influenza A virus A/WSN/33 (H1N1) replication results in G0/G1-phase accumulation of infected cells and that this accumulation is caused by the prevention of cell cycle entry from G0/G1 phase into S phase. Consistent with the G0/G1-phase accumulation, the amount of hyperphosphorylated retinoblastoma protein, a necessary active form for cell cycle progression through late G1 into S phase, decreased after infection with A/WSN/33 (H1N1) virus. In addition, other key molecules in the regulation of the cell cycle, such as p21, cyclin E, and cyclin D1, were also changed and showed a pattern of G0/G1-phase cell cycle arrest. It is interesting that increased viral protein expression and progeny virus production in cells synchronized in the G0/G1 phase were observed compared to those in either unsynchronized cells or cells synchronized in the G2/M phase. G0/G1-phase cell cycle arrest is likely a common strategy, since the effect was also observed in other strains, such as H3N2, H9N2, PR8 H1N1, and pandemic swine H1N1 viruses. These findings, in all, suggest that influenza A virus may provide favorable conditions for viral protein accumulation and virus production by inducing a G0/G1-phase cell cycle arrest in infected cells.

scholarly journals Murine Norovirus Replication Induces G0/G1Cell Cycle Arrest in Asynchronously Growing Cells

2015 ◽  
Vol 89 (11) ◽  
pp. 6057-6066 ◽  
Author(s):  
Colin Davies ◽  
Chris M. Brown ◽  
Dana Westphal ◽  
Joanna M. Ward ◽  
Vernon K. Ward
Keyword(s):  
Cell Cycle ◽  
Viral Replication ◽  
Host Cell ◽  
Virus Replication ◽  
Cell Cycle Progression ◽  
Cycle Phase ◽  
Murine Norovirus ◽  
Cycle Progression ◽  
Infected Cells ◽  
Favorable Conditions

ABSTRACTMany viruses replicate most efficiently in specific phases of the cell cycle, establishing or exploiting favorable conditions for viral replication, although little is known about the relationship between caliciviruses and the cell cycle. Microarray and Western blot analysis of murine norovirus 1 (MNV-1)-infected cells showed changes in cyclin transcript and protein levels indicative of a G1phase arrest. Cell cycle analysis confirmed that MNV-1 infection caused a prolonging of the G1phase and an accumulation of cells in the G0/G1phase. The accumulation in G0/G1phase was caused by a reduction in cell cycle progression through the G1/S restriction point, with MNV-1-infected cells released from a G1arrest showing reduced cell cycle progression compared to mock-infected cells. MNV-1 replication was compared in populations of cells synchronized into specific cell cycle phases and in asynchronously growing cells. Cells actively progressing through the G1phase had a 2-fold or higher increase in virus progeny and capsid protein expression over cells in other phases of the cell cycle or in unsynchronized populations. These findings suggest that MNV-1 infection leads to prolonging of the G1phase and a reduction in S phase entry in host cells, establishing favorable conditions for viral protein production and viral replication. There is limited information on the interactions between noroviruses and the cell cycle, and this observation of increased replication in the G1phase may be representative of other members of theCaliciviridae.IMPORTANCENoroviruses have proven recalcitrant to growth in cell culture, limiting our understanding of the interaction between these viruses and the infected cell. In this study, we used the cell-culturable MNV-1 to show that infection of murine macrophages affects the G1/S cell cycle phase transition, leading to an arrest in cell cycle progression and an accumulation of cells in the G0/G1phase. Furthermore, we show that MNV replication is enhanced in the G1phase compared to other stages of the cell cycle. Manipulating the cell cycle or adapting to cell cycle responses of the host cell is a mechanism to enhance virus replication. To the best of our knowledge, this is the first report of a norovirus interacting with the host cell cycle and exploiting the favorable conditions of the G0/G1phase for RNA virus replication.

scholarly journals Eimeria tenella ROP kinase EtROP1 induces G0/G1 cell cycle arrest and inhibits host cell apoptosis

2019 ◽  
Vol 21 (7) ◽  
Author(s):  
Mamadou Amadou Diallo ◽  
Alix Sausset ◽  
Audrey Gnahoui‐David ◽  
Adeline Ribeiro E Silva ◽  
Aurélien Brionne ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Host Cell ◽  
Cell Apoptosis ◽  
Eimeria Tenella ◽  
Cycle Arrest ◽  
Host Cell Apoptosis ◽  
G1 Cell Cycle Arrest

scholarly journals The Novel Nature Microtubule Inhibitor Ivalin Induces G2/M Arrest and Apoptosis in Human Hepatocellular Carcinoma SMMC-7721 Cells In Vitro

Medicina ◽  
2019 ◽  
Vol 55 (8) ◽  
pp. 470 ◽  
Author(s):  
Fangyuan Liu ◽  
Shiqi Lin ◽  
Caiyun Zhang ◽  
Jiahui Ma ◽  
Zhuo Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Western Blotting ◽  
Network Formation ◽  
Cyclin B1 ◽  
Human Hepatocellular Carcinoma ◽  
Microtubule Depolymerization ◽  
Microtubule Network ◽  
Cycle Arrest

Background and Objectives: Microtubules are an attractive target for cancer chemotherapy. Previously, we reported that Ivalin exhibited excellent anti-migration and anti-invasion activities in human breast cancer cells. Here, we examined the microtubule inhibition effect of Ivalin in human hepatocellular carcinoma SMMC-7721 cells. Materials and Methods: We used the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate the cell proliferation effect of Ivalin and flow cytometry analysis to detect the apoptotic and cell cycle arrest effects of Ivalin. Immunofluorescence staining was used to measure the effect of Ivalin on the cytoskeleton network, and Western blotting was used to detect the expression levels of Bax, Bcl-2, Cdc2, phosphor-Cdc2, Cdc25A, Cyclin B1, and tubulin. Results: Ivalin induced cell cycle G2/M arrest and subsequent triggered apoptosis in human hepatocellular carcinoma SMMC-7721 cells. Furthermore, microtubules were shown to be involved in Ivalin-meditated apoptosis. In this connection, Ivalin treatment suppressed cellular microtubule network formation by regulating microtubule depolymerization. Moreover, Western blotting revealed Cdc25A and Cyclin B1 were upregulated in Ivalin-meditated cell cycle arrest. Subsequently, the induction of Bax (a proapoptotic protein) and reduction of Bcl-2 (an anti-apoptotic protein) expression were observed in Ivalin-treated SMMC-7721 cells. Conclusion: Ivalin induced microtubule depolymerization, then blocked cells in mitotic phase, and eventually resulted in apoptosis in SMMC-7721 cells. Collectively, these data indicate that Ivalin, acting as a novel inhibitor of microtubules, could be considered as a promising lead in anticancer drug development.

SMBA1, a Bax Activator, Induces Cell Cycle Arrest and Apoptosis in Malignant Glioma Cells

Pharmacology ◽  
2019 ◽  
Vol 105 (3-4) ◽  
pp. 164-172
Author(s):  
Shuangbo Fan ◽  
Qian Xu ◽  
Liang Wang ◽  
Yulin Wan ◽  
Sheng Qiu
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Biological Effects ◽  
Cyclin B1 ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
Cycle Arrest ◽  
Intrinsic Apoptosis Pathway ◽  
Induced Apoptosis ◽  
Dose Dependent

SMBA1 (small-molecule Bax agonists 1), a small molecular activator of Bax, is a potential anti-tumour agent. In the present study, we investigated the biological effects of SMBA1 on glioblastoma (GBM) cells. SMBA1 reduced the viabilities of U87MG, U251 and T98G cells in a time- and dose-dependent manner. Moreover, treatment with SMBA1 induced cell cycle arrest at the G2/M phase transition, accompanied by the downregulation of Cdc25c and cyclin B1 and the upregulation of p21. SMBA1 also induced apoptosis of GBM cells in a dose-dependent manner. Mechanistically, SMBA1 induced apoptosis via the intrinsic pathway. Silencing of Bax or ectopic expression of Bcl-2 significantly inhibited SMBA1-induced apoptosis. Moreover, SMBA1 inhibited the growth of U87MG xenograft tumours in vivo. Overall, SMBA1 shows anti-proliferative effects against GBM cells through activation of the intrinsic apoptosis pathway.

scholarly journals Human Immunodeficiency Virus Type 1 Vpr-Dependent Cell Cycle Arrest through a Mitogen-Activated Protein Kinase Signal Transduction Pathway

2005 ◽  
Vol 79 (17) ◽  
pp. 11366-11381 ◽  
Author(s):  
Naoto Yoshizuka ◽  
Yuko Yoshizuka-Chadani ◽  
Vyjayanthi Krishnan ◽  
Steven L. Zeichner
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Human Immunodeficiency Virus ◽  
Cell Cycle Arrest ◽  
Host Cell ◽  
Human Immunodeficiency Virus Type ◽  
Erk Pathway ◽  
Cycle Arrest ◽  
Immunodeficiency Virus

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Vpr protein has important functions in advancing HIV pathogenesis via several effects on the host cell. Vpr mediates nuclear import of the preintegration complex, induces host cell apoptosis, and inhibits cell cycle progression at G2, which increases HIV gene expression. Some of Vpr's activities have been well described, but some functions, such as cell cycle arrest, are not yet completely characterized, although components of the ATR DNA damage repair pathway and the Cdc25C and Cdc2 cell cycle control mechanisms clearly play important roles. We investigated the mechanisms underlying Vpr-mediated cell cycle arrest by examining global cellular gene expression profiles in cell lines that inducibly express wild-type and mutant Vpr proteins. We found that Vpr expression is associated with the down-regulation of genes in the MEK2-ERK pathway and with decreased phosphorylation of the MEK2 effector protein ERK. Exogenous provision of excess MEK2 reverses the cell cycle arrest associated with Vpr, confirming the involvement of the MEK2-ERK pathway in Vpr-mediated cell cycle arrest. Vpr therefore appears to arrest the cell cycle at G2/M through two different mechanisms, the ATR mechanism and a newly described MEK2 mechanism. This redundancy suggests that Vpr-mediated cell cycle arrest is important for HIV replication and pathogenesis. Our findings additionally reinforce the idea that HIV can optimize the host cell environment for viral replication.

scholarly journals Bortezomib Is Effective in Treating T-ALL, Inducting G2/M Cell Cycle Arrest and WEE1 Downregulation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4360-4360
Author(s):  
SIN Chun-fung ◽  
Timothy Ming-hun Wan ◽  
Aarmann Anil Mohinani Mohan ◽  
Yinxia Qiu ◽  
Anan Jiao
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Line ◽  
Cell Lines ◽  
Mechanism Of Action ◽  
Therapeutic Efficacy ◽  
Cyclin B1 ◽  
M Cell ◽  
Cycle Arrest ◽  
Cell Cycle Modulation

Abstract T lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy with poor outcome, especially for relapse/refractory disease. Early T- cell precursor acute lymphoblastic leukaemia (ETP-ALL) is a recently identified subtype of T-ALL with worse treatment outcome compared with other subtypes of T-ALL and treatment options are limited. T-ALL frequently harbors genetic aberrations leading to cell cycle dysregulation and it is one of the major molecular pathogenesis of T-ALL. WEE1 is a protein kinase that is responsible for inhibiting mitosis with unrepaired damaged DNA via inactivating CDK1. WEE1 is highly express in adult T-ALL and its overexpression is associated with adverse prognosis in various cancers. Inhibiting WEE1 expression is a novel approach of therapy. Bortezomib is a 26S proteosome inhibitor and it is FDA approved for treating plasma cell myeloma and mantle cell lymphoma. Bortezomib had been demonstrated therapeutic efficacy in clinical setting for relapse/refractory paediatric T-ALL and B-ALL when combined with chemotherapy. Despite its therapeutic efficacy in clinical studies, the mechanism of action of Bortezomib in T-ALL remain uncertain. The role of Bortezomib in cell cycle modulation had not been established in T-ALL. Moreover, it had not been demonstrated that the effect of Bortezomib in WEE1 expression in T-ALL. Here, we present our study that demonstrated the therapeutic efficacy of Bortezomib in treating T-ALL via cell cycle modulation and downregulation of WEE1 by Bortezomib. T-ALL cell lines including MOLT16, MOLT4, LOUCY and CEM were used in the study. Cell viability was measured by trypan blue. Apoptosis and cell cycle analysis were measured by flow cytometry. Western blot of WEE1, p53, cyclin B1, p21 and p27 were performed. Our result showed that Bortezomib reduce the cell viability of T-ALL cell lines in dose and time-dependent manner. Bortezomib was also sensitive towards LOUCY, a T-ALL cell line with ETP-ALL phenotype. It implied that Bortezomib could be a promising therapy for ETP-ALL. Bortezomib also triggered apoptosis in various T-ALL and the effect of apoptosis was more pronounced after 72 hours of treatment when compared with 24-hour. Again, Bortezomib was able to induce apoptosis in LOUCY cell line. G2/M cell cycle arrest was observed in various T-ALL upon treatment of Bortezomib. The effect on cell cycle modulation was also observed in LOUCY cell line. The protein expression of p21 and p27 were increased after the treatment of Bortezomib. The level of cyclin B1 was increased also. There was upregulation of p53 after Bortezomib treatment. Strikingly, the protein expression level of WEE1 was reduced. The findings of WEE1 downregulation by Bortezomib is a novel findings. We also showed that Bortezomib downregulate WEE1 mRNA expression by quantitative PCR. Our study showed that Bortezomib is active against T-ALL cell lines, including ETP-ALL cell line, LOUCY and modulates cell cycle with G2/M arrest. Bortezomib had been shown to increase the level of p21, p27 and cyclin B1 and induced G2/M cell cycle arrest in glioblastoma cells. However, studies on cell cycle modulation by Bortezomib in T-ALL are scarce. Here, we demonstrated Bortezomib stabilized p21, p27 and upregulation of cyclin B1 in T-ALL as well, which could account for the G2/M cell cycle arrest. We first showed that downregulation of WEE1 after treatment with Bortezomib, in protein level as well as in mRNA level. Recent study showed that inhibition of WEE1 is a novel target of therapy in T-ALL. WEE1 is upregulated in T-ALL to prevent entry of mitosis with unrepaired damaged DNA. The downregulation of WEE1 by Bortezomib as showed by our study could reverse its effect and leads to apoptosis of leukaemic cells. In summary, our study provides the insight on mechanism of action of Bortezomib in modulating cell cycle in T-ALL. Moreover, it is the first study to demonstrate WEE1 downregulation by Bortezomib in T-ALL. These findings not only enhance our understanding of mechanism of action of Bortezomib in T-ALL, but also rationalized the use of certain synergistics combination therapy with Bortezomib in treating T-ALL, e.g., chemotherapeutic agents, PARP inhibitors which could damage DNA of leukaemic cells. Further research is needed to explore those combination therapy in T-ALL and molecular mechanism of downregulation of WEE1 by Bortezomib in T-ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ghrelin enhances cisplatin sensitivity in HO-8910 PM human ovarian cancer cells

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yun Leng ◽  
Can Zhao ◽  
Guoliang Yan ◽  
Shuangyue Xu ◽  
Yinggui Yang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cell Cycle Arrest ◽  
Cyclin B1 ◽  
Inhibitory Effect ◽  
S Phase ◽  
Phase Cell ◽  
Ovarian Cancer Cells ◽  
Cycle Arrest

Abstract Background Resistance to platinum-based chemotherapy is one of the crucial problems in ovarian cancer treatment. Ghrelin, a widely distributed peptide hormone, participates in a series of cancer progression. The aim of this study is to determine whether ghrelin influences the sensitivity of ovarian cancer to cisplatin, and to demonstrate the underlying mechanism. Methods The anti-tumor effects of ghrelin and cisplatin were evaluated with human ovarian cancer cells HO-8910 PM in vitro or in vivo. Cell apoptosis and cell cycle were analyzed via flow cytometry assay. The signaling pathway and the expression of cell cycle protein were analyzed with Western Blot. Results Our results showed that treatment with ghrelin specifically inhibited cell proliferation of HO-8910 PM and sensitized these cells to cisplatin via S phase cell cycle arrest, and enhanced the inhibitory effect of cisplatin on tumor growth of HO-8910 PM derived xenografts in vivo. Treatment with ghrelin inhibited the expression of p-Erk1/2 and p-p38, which was opposite the effect of cisplatin. However, under the treatment of ghrelin, cisplatin treatment exhibited a stronger effect on inhibiting P21 expression, upregulating p-CDK1 and cyclin B1 expression, and blocking cell cycle progression. Mechanistically, ghrelin promoted S phase cell cycle arrest and upregulated p-CDK1 and cyclin B1 expression induced by cisplatin via inhibition of p38. Conclusion This study revealed a specifically inhibitory effect of ghrelin on platinum-resistance via suppressing p-P38 and subsequently promoting p-CDK1 mediated cell cycle arrest in HO-8910 PM.

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