PAK4 confers the malignance of cervical cancers and contributes to the cisplatin-resistance in cervical cancer cells via PI3K/AKT pathway

Abstract Background CSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet. Methods Data from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 and clinical relevance in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR–CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. The biological behaviors were analyzed by CCK8, clone formation assay, 3-D spheroid generation assay and cell cycle assay. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. MLN4924 was given in Siha and Hela with CSN5 overexpression. Results We found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells. Conclusions Our findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.

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The Potential Oncogenic and MLN4924-Resistant Effects of CSN5 on Cervical Cancer Cells

10.21203/rs.3.rs-550782/v1 ◽

2021 ◽

Author(s):

Huilin Zhang ◽

Ping He ◽

Qing Zhou ◽

Yan Lu ◽

Bingjian Lu

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Cell ◽

Cervical Cancer Cell ◽

Cervical Cancers ◽

Cervical Cancer Cells

Abstract BackgroundsCSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet.MethodsData from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR-CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. CCK8, clone formation assay and cell cycle assay were also employed. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. Moreover, MLN4924 was applied in Siha and Hela with CSN5 overexpression.ResultsWe found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells.ConclusionsOur findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.

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Inhibiting the cytoplasmic location of HMGB1 reverses cisplatin resistance in human cervical cancer cells

Molecular Medicine Reports ◽

10.3892/mmr.2016.6003 ◽

2016 ◽

Vol 15 (1) ◽

pp. 488-494 ◽

Cited By ~ 13

Author(s):

Jiyi Xia ◽

Xiaolan Yu ◽

Xueqin Song ◽

Gang Li ◽

Xiguang Mao ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Cervical Cancer Cells ◽

Human Cervical Cancer Cells ◽

Cytoplasmic Location ◽

Human Cervical Cancer

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MicroRNA-7-5p Promotes Cisplatin Resistance of Cervical Cancer Cells and Modulation of Cellular Energy Homeostasis by Regulating the Expression of the PARP-1 and BCL2 Genes

Medical Science Monitor ◽

10.12659/msm.910969 ◽

2018 ◽

Vol 24 ◽

pp. 6506-6516 ◽

Cited By ~ 12

Author(s):

Fengxia Yang ◽

Li Guo ◽

Yujing Cao ◽

Shizhen Li ◽

Jianhua Li ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Energy Homeostasis ◽

Cisplatin Resistance ◽

Cellular Energy ◽

Cervical Cancer Cells ◽

Parp 1

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CD59 receptor targeted delivery of miRNA-1284 and Cisplatin-loaded liposomes for effective therapeutic efficacy against cervical cancers

10.21203/rs.2.22723/v1 ◽

2020 ◽

Author(s):

Li Wang ◽

Ting-Ting Liang

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Targeted Delivery ◽

Blood Circulation ◽

Anticancer Effect ◽

Killing Effect ◽

Cervical Cancers ◽

Cervical Cancer Cells ◽

Dependent Cell ◽

Cell Killing Effect

Abstract Co-delivery of two different therapeutics (miRNA-1284 and cisplatin (CDDP)) into the cancer cells in a single nanocarrier provides new dimension to the cancer treatment. In this study, we have designed the CD59sp-conjugated miRNA-1284/cisplatin(CDDP)-loaded liposomes for the enhanced therapeutic effect against cervical cancers. Compared with miRNA-1284/CDDP-loaded liposomes (LP-miCDDP), CD59 antibody-conjugated LP-miCDDP (CD/LP-miCDDP) showed a significantly higher cytotoxicity in HeLa cells. Notably, MiR-1284 showed a typical concentration-dependent cell killing effect in the cervical cancer cells owing to the downregulation of HMGB1. Flow cytometer analysis showed that CD/LP-miCDDP resulted in maximum apoptosis effect (~60%) compared to CDDP (~20%) or miR-1284 (~12%) treated cells indicating the superior anticancer effect in the cancer cells. Importantly, CD/LP-miCDDP significantly prolonged the blood circulation of encapsulated drug in rats with significantly higher AUC (o-t) , t 1/2 and lower CL compared to that of free CDDP. Overall, results demonstrated that targeted and synergistic co-delivery of therapeutic components could be promising in cervical cancer therapy.

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Enhancer of mRNA Decapping protein 4 (EDC4) interacts with replication protein a (RPA) and contributes to Cisplatin resistance in cervical Cancer by alleviating DNA damage

Hereditas ◽

10.1186/s41065-020-00154-w ◽

2020 ◽

Vol 157 (1) ◽

Author(s):

Xiaoling Wu ◽

Youwen Zhong ◽

Qing Chen ◽

Xin Zhang ◽

Hua Zhang

Keyword(s):

Cervical Cancer ◽

Dna Damage ◽

Cell Growth ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Protein A ◽

Replication Protein A ◽

Replication Protein ◽

Mrna Decapping ◽

Cervical Cancer Cells

Abstract Background Cervical cancer (CC) is the third most common gynecological malignancy around the world. Cisplatin is an effective drug, but cisplatin resistance is a vital factor limiting the clinical usage of cisplatin. Enhancer of mRNA decapping protein 4 (EDC4) is a known regulator of mRNA decapping, which was related with genome stability and sensitivity of drugs. This research was to investigate the mechanism of EDC4 on cisplatin resistance in CC. Two human cervical cancer cell lines, HeLa and SiHa, were used to investigate the role of EDC4 on cisplatin resistance in vitro. The knockdown or overexpression of EDC4 or replication protein A (RPA) in HeLa or SiHa cells was performed by transfection. Cell viability was analyzed by MTT assay. The growth of cancer cells was evaluated by colony formation assay. DNA damage was measured by γH2AX (a sensitive DNA damage response marker) immunofluorescent staining. The binding of EDC4 and RPA was analyzed by immunoprecipitation. Results EDC4 knockdown in cervical cancer cells (HeLa and SiHa) enhanced cisplatin sensitivity and cisplatin induced cell growth inhibition and DNA damage. EDC4 overexpression reduced DNA damage caused by cisplatin and enhanced cell growth of cervical cancer cells. EDC4 could interact with RPA and promote RPA phosphorylation. RPA knockdown reversed the inhibitory effect of EDC4 on cisplatin-induced DNA damage. Conclusion The present results indicated that EDC4 is responsible for the cisplatin resistance partly through interacting with RPA in cervical cancer by alleviating DNA damage. This study indicated that EDC4 or RPA may be novel targets to combat chemotherapy resistance in cervical cancer. Graphical abstract

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