scholarly journals Inhibition of Kpnβ1 mediated nuclear import enhances cisplatin chemosensitivity in cervical cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ru-pin Alicia Chi ◽  
Pauline van der Watt ◽  
Wei Wei ◽  
Michael J. Birrer ◽  
Virna D. Leaner
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Cell Viability ◽  
Cancer Cells ◽  
Combination Treatment ◽  
Nuclear Import ◽  
Reporter Activity ◽  
Cervical Cancer Cells ◽  
Cisplatin Sensitivity ◽  
Pre Treatment

Abstract Background Inhibition of nuclear import via Karyopherin beta 1 (Kpnβ1) shows potential as an anti-cancer approach. This study investigated the use of nuclear import inhibitor, INI-43, in combination with cisplatin. Methods Cervical cancer cells were pre-treated with INI-43 before treatment with cisplatin, and MTT cell viability and apoptosis assays performed. Activity and localisation of p53 and NFκB was determined after co-treatment of cells. Results Pre-treatment of cervical cancer cells with INI-43 at sublethal concentrations enhanced cisplatin sensitivity, evident through decreased cell viability and enhanced apoptosis. Kpnβ1 knock-down cells similarly displayed increased sensitivity to cisplatin. Combination index determination using the Chou-Talalay method revealed that INI-43 and cisplatin engaged in synergistic interactions. p53 was found to be involved in the cell death response to combination treatment as its inhibition abolished the enhanced cell death observed. INI-43 pre-treatment resulted in moderately stabilized p53 and induced p53 reporter activity, which translated to increased p21 and decreased Mcl-1 upon cisplatin combination treatment. Furthermore, cisplatin treatment led to nuclear import of NFκB, which was diminished upon pre-treatment with INI-43. NFκB reporter activity and expression of NFκB transcriptional targets, cyclin D1, c-Myc and XIAP, showed decreased levels after combination treatment compared to single cisplatin treatment and this associated with enhanced DNA damage. Conclusions Taken together, this study shows that INI-43 pre-treatment significantly enhances cisplatin sensitivity in cervical cancer cells, mediated through stabilization of p53 and decreased nuclear import of NFκB. Hence this study suggests the possible synergistic use of nuclear import inhibition and cisplatin to treat cervical cancer.

scholarly journals Inhibition of Kpn β 1 Mediated Nuclear Import Enhances Cisplatin Chemosensitivity in Cervical Cancer.

2020 ◽  
Author(s):  
Ru-pin Alicia Chi ◽  
Pauline van der Watt ◽  
Wei Wei ◽  
Michael Birrer ◽  
Virna Leaner
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Cell Viability ◽  
Cancer Cells ◽  
Combination Treatment ◽  
Nuclear Import ◽  
Reporter Activity ◽  
Cervical Cancer Cells ◽  
Cisplatin Sensitivity ◽  
Pre Treatment

Abstract Background: Inhibition of nuclear import via Karyopherin beta 1 (Kpnβ1) shows potential as an anti-cancer approach. This study investigated the use of nuclear import inhibitor, INI-43, in combination with cisplatin. Methods: Cervical cancer cells were pre-treated with INI-43 before treatment with cisplatin, and MTT cell viability and apoptosis assays performed. Activity and localisation of p53 and NFκB was determined after co-treatment of cells.Results: Pre-treatment of cervical cancer cells with INI-43 at sublethal concentrations enhanced cisplatin sensitivity, evident through decreased cell viability and enhanced apoptosis. Kpnβ1 knock-down cells similarly displayed increased sensitivity to cisplatin. Combination index determination using the Chou-Talalay method revealed that INI-43 and cisplatin engaged in synergistic interactions. p53 was found to be involved in the cell death response to combination treatment as its inhibition abolished the enhanced cell death observed. INI-43 pre-treatment resulted in moderately stabilized p53 and induced p53 reporter activity, which translated to increased p21 and decreased Mcl-1 upon cisplatin combination treatment. Furthermore, cisplatin treatment led to nuclear import of NFκB, which was diminished upon pre-treatment with INI-43. NFκB reporter activity and expression of NFκB transcriptional targets, cyclin D1, c-Myc and XIAP, showed decreased levels after combination treatment compared to single cisplatin treatment and this associated with enhanced DNA damage. Conclusions: Taken together, this study shows that INI-43 pre-treatment significantly enhances cisplatin sensitivity in cervical cancer cells, mediated through stabilization of p53 and decreased nuclear import of NFκB. Hence this study suggests the possible synergistic use of nuclear import inhibition and cisplatin to treat cervical cancer.

scholarly journals Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells

2018 ◽  
Vol 46 (1) ◽  
pp. 322-334 ◽  
Author(s):  
Chia-Liang Lin ◽  
Chien-Hsing Lee ◽  
Chien-Min Chen ◽  
Chun-Wen Cheng ◽  
Pei-Ni Chen ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Cell Viability ◽  
Er Stress ◽  
Cancer Cells ◽  
Cervical Cancer Cells ◽  
Stress Dependent ◽  
Human Cervical Cancer Cells ◽  
Human Cervical Cancer

Background/Aims: Protodioscin (PD) is a steroidal saponin with anti-cancer effects on a number of cancer cells, but the anti-tumor effects and mechanism of action of PD on human cervical cancer cells is unclear. Methods: We determined cell viability using the MTT assay. Cell death, mitochondrial membrane potential (MMP), intracellular reactive oxygen species (ROS) generation, and endoplasmic reticulum (ER) stress were measured on a flow cytometry. Caspase activation, ER stress, and MMP-dependent apoptosis proteins in cervical cancer cells in response to PD were determined by Western blot analysis. The ability of ATF4 binding to ChIP promoter was measured using the ChIP assay. Results: We demonstrated that PD inhibits cell viability, causes a loss of mitochondrial function, and induces apoptosis, as evidenced by up-regulation of caspase-8, -3, -9, -PARP, and Bax activation, and down-regulation of Bcl-2 expression. PD was shown to induce ROS and the ER stress pathway, including GRP78, p-eIF-2α, ATF4, and CHOP. Pre-treatment with NAC, a ROS production inhibitor, significantly reduced ER stress and apoptosis-related proteins induced by PD. Transfection of GRP78/CHOP-siRNA effectively inhibited PD-induced ER stress-dependent apoptosis. Moreover, treatment with PD significantly increased p38 and JNK activation. Co-administration of a JNK inhibitor (SP600125) or p38 inhibitor (SB203580) abolished cell death and ER stress effects during PD treatment. In addition, PD induced the expression of nuclear ATF4 and CHOP, as well as the binding ability of ATF4 to the CHOP promoter. Conclusion: Our results suggest that PD is a promising therapeutic agent for the treatment of human cervical cancer.

scholarly journals Chloroform fraction of Chaetomorpha brachygona, a marine green alga from Indian Sundarbans inducing autophagy in cervical cancer cells in vitro

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Indira Majumder ◽  
Subhabrata Paul ◽  
Anish Nag ◽  
Rita Kundu
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Green Alga ◽  
Chloroform Fraction ◽  
Anticancer Activities ◽  
Siha Cell Line ◽  
Cervical Cancer Cells ◽  
Marine Green Alga

AbstractSundarbans Mangrove Ecosystem (SME) is a rich repository of bioactive natural compounds, with immense nutraceutical and therapeutic potential. Till date, the algal population of SME was not explored fully for their anticancer activities. Our aim is to explore the potential of these algal phytochemicals against the proliferation of cervical cancer cells (in vitro) and identify the mode of cell death induced in them. In the present work, the chloroform fraction of marine green alga, Chaetomorpha brachygona was used on SiHa cell line. The algal phytochemicals were identified by GCMS, LCMS and column chromatography and some of the identified compounds, known for significant anticancer activities, have shown strong Bcl-2 binding capacity, as analyzed through molecular docking study. The extract showed cytostatic and cytotoxic activity on SiHa cells. Absence of fragmented DNA, and presence of increased number of acidic vacuoles in the treated cells indicate nonapoptotic cell death. The mode of cell death was likely to be autophagic, as indicated by the enhanced expression of Beclin 1 and LC3BII (considered as autophagic markers) observed by Western blotting. The study indicates that, C. brachygona can successfully inhibit the proliferation of cervical cancer cells in vitro.

scholarly journals Caspase-Independent Cell Death by Arsenic Trioxide in Human Cervical Cancer Cells

2004 ◽  
Vol 64 (24) ◽  
pp. 8960-8967 ◽  
Author(s):  
Young-Hee Kang ◽  
Min-Jung Yi ◽  
Min-Jung Kim ◽  
Moon-Taek Park ◽  
Sangwoo Bae ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Arsenic Trioxide ◽  
Cervical Cancer Cells ◽  
Human Cervical Cancer Cells ◽  
Human Cervical Cancer

scholarly journals The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 108 ◽  
Author(s):  
I-Lun Hsin ◽  
Ying-Hsiang Chou ◽  
Wei-Li Hung ◽  
Jiunn-Liang Ko ◽  
Po-Hui Wang
Keyword(s):  
Cervical Cancer ◽  
Synergistic Effect ◽  
Cancer Cells ◽  
Arsenic Trioxide ◽  
Combination Treatment ◽  
Combined Treatment ◽  
B Cell Lymphoma ◽  
Uterine Cervical Cancer ◽  
Cervical Cancer Cells ◽  
Mediated Reduction

ABT-737, a B cell lymphoma-2 (Bcl-2) family inhibitor, activates apoptosis in cancer cells. Arsenic trioxide is an apoptosis activator that impairs cancer cell survival. The aim of this study was to evaluate the effect of a combination treatment with ABT-737 and arsenic trioxide on uterine cervical cancer cells. MTT (3-(4,5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) assay revealed that ABT-737 and arsenic trioxide induced a synergistic effect on uterine cervical cancer cells. Arsenic trioxide enhanced ABT-737-induced apoptosis and caspase-7 activation and the ABT-737-mediated reduction of anti-apoptotic protein Mcl-1 in Caski cells. Western blot assay revealed that arsenic trioxide promoted the ABT-737-mediated reduction of CDK6 and thymidylate synthetase in Caski cells. Arsenic trioxide promoted ABT-737-inhibited mitochondrial membrane potential and ABT-737-inhibited ANT expression in Caski cells. However, ABT-737-elicited reactive oxygen species were not enhanced by arsenic trioxide. The combined treatment induced an anti-apoptosis autophagy in SiHa cells. This study is the first to demonstrate that a combination treatment with ABT-737 and arsenic trioxide induces a synergistic effect on uterine cervical cancer cells through apoptosis. Our findings provide new insights into uterine cervical cancer treatment.

scholarly journals MDC1 depletion promotes cisplatin induced cell death in cervical cancer cells

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Neeru Singh ◽  
Rashmi Bhakuni ◽  
Dimple Chhabria ◽  
Sivapriya Kirubakaran
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cervical Cancer Cells

Methyl jasmonate induces cell death with mixed characteristics of apoptosis and necrosis in cervical cancer cells

2008 ◽  
Vol 271 (1) ◽  
pp. 34-46 ◽  
Author(s):  
Tatiana Kniazhanski ◽  
Anna Jackman ◽  
Alina Heyfets ◽  
Pinhas Gonen ◽  
Eliezer Flescher ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Methyl Jasmonate ◽  
Cancer Cells ◽  
Cervical Cancer Cells ◽  
Apoptosis And Necrosis

Epigenetic regulation of KLK7 gene expression in pancreatic and cervical cancer cells

2016 ◽  
Vol 397 (11) ◽  
pp. 1135-1146 ◽  
Author(s):  
Ilangovan Raju ◽  
Gur P. Kaushal ◽  
Randy S. Haun
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Promoter Region ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Reporter Activity ◽  
Promoter Deletion Analysis ◽  
Cervical Cancer Cells ◽  
Chip Analysis

Abstract Kallikrein-related peptidase 7 (KLK7) is a serine protease encoded within the kallikrein gene cluster located on human chromosome region 19q13.3-13.4. KLK7 is overexpressed in human pancreatic ductal adenocarcinomas (PDACs), but not in normal pancreas. Examination of KLK7 mRNA levels in pancreatic cancer cell lines revealed that it is readily detected in MIA PaCa-2 and PK-1 cells, but not in Panc-1 cells. Treatment of Panc-1 cells with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) significantly induced KLK7 mRNA expression. Similarly, KLK7 is highly expressed in cervical cancer cells, but its expression in the human cervical cancer cell line HeLa is only detected following TSA treatment. Promoter deletion analysis revealed that the proximal -238 promoter region, containing a putative Sp1-binding site, was sufficient for TSA activation of luciferase reporter activity, which was abrogated by the disruption of the Sp1-binding sequence. Consistent with the notion that TSA induced KLK7 expression via Sp1, co-expression of Sp1 with the KLK7-promoter/luciferase construct produced a significant increase in reporter activity. Chromatin immunoprecipitation (ChIP) analysis revealed enriched Sp1 occupancy on the KLK7 promoter following TSA treatment. Similarly, ChIP analysis showed the histone active mark, H3K4Me3, in the KLK7 promoter region was significantly increased after exposure to TSA.

scholarly journals Utilization of a cell-penetrating peptide-adaptor for delivery of HPV protein E2 into cervical cancer cells to arrest cell growth and promote cell death

2020 ◽  
Author(s):  
Julia C. LeCher ◽  
Hope L. Didier ◽  
Robert L. Dickson ◽  
Lauren R. Slaughter ◽  
Juana C. Bejarano ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Penetrating Peptides ◽  
Viral Integration ◽  
E2 Protein ◽  
Cell Penetrating ◽  
Cervical Cancer Cells ◽  
E6 And E7

AbstractCervical cancer is the second leading cause of cancer deaths in women worldwide. Human papillomavirus (HPV) is the causative agent of nearly all forms of cervical cancer, which arises upon viral integration into the host genome and concurrent loss of regulatory gene E2. E2 protein regulates viral oncoproteins E6 and E7. Loss of E2 upon viral integration results in unregulated expression and activity of E6 and E7, which promotes carcinogenesis. Previous studies using gene-based delivery show that reintroduction of E2 into cervical cancer cell lines can reduce proliferative capacity and promote apoptosis. However, owing in part to limitations on transfection in vivo, E2 reintroduction has yet to achieve therapeutic usefulness. A promising new approach is protein-based delivery systems utilizing cell-penetrating peptides (CPPs). CPPs readily traverse the plasma membrane and are able to carry with them biomolecular ‘cargos’ to which they are attached. Though more than two decades of research have been dedicated to their development for delivery of biomolecular therapeutics, the full potential of CPPs has yet to be realized as the field is hindered by the tendency of CPP-linked cargos to be trapped in endosomes as well as having significant off-target potential in vivo. Using a CPP-adaptor system that reversibly binds cargo thereby overcoming the endosomal entrapment that hampers other CPP methods, bioactive E2 protein was delivered into living cervical cancer cells, resulting in inhibition of cellular proliferation and promotion of cell death in a time- and dose-dependent manner. The results suggest that this nucleic acid- and virus-free delivery method could be harnessed to develop novel, effective protein therapeutics for treatment of cervical cancer.

Sign in / Sign up

Export Citation Format

Share Document