NTNG1 Modulates Cisplatin Resistance in Epithelial Ovarian Cancer Cells via the GAS6/AXL/Akt Pathway

Cisplatin resistance is a challenge in the treatment of epithelial ovarian cancer. Here, clinical data showed that the level of netrin-G1 (NTNG1) in cisplatin-resistant cancer was higher than that in cisplatin-sensitive cancer (2.2-fold, p = 0.005); patients with a high NTNG1 level in cancer tissues had shorter progression-free survival (11.0 vs. 25.0 months, p = 0.010) and platinum-free interval (5.0 vs. 20.0 months, p = 0.021) compared with patients with a low level. Category- or stage-adjusted analyses demonstrated that the association between the NTNG1 level and prognosis occurred in type II or FIGO III/IV cancer. The basal level of NTNG1 in SKOV3/DDP cells (a cisplatin-resistant subline) was higher than that in SKOV3 cells; therefore, NTNG1 was overexpressed in SKOV3 cells, or silenced in SKOV3/DDP cells. Knocking in NTNG1 reduced the action of cisplatin to decrease cell death and apoptosis of SKOV3 cells, accompanied by upregulation of p-AXL, p-Akt and RAD51; however, opposite effects were observed in SKOV3/DDP cells after knocking down NTNG1. Co-immunoprecipitation demonstrated that NTNG1 bound GAS6/AXL. Silencing NTNG1 enhanced cisplatin effects in vivo, decreasing tumor volume/mass. These data suggested that a high NTNG1 level can result in cisplatin resistance in ovarian cancer cells via the GAS6/AXL/Akt pathway and that NTNG1 may be a useful target to overcome resistance.

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CNDP2 Acts as an Activator for Human Ovarian Cancer Growth and Metastasis via the PI3K/AKT Pathway

Technology in Cancer Research & Treatment ◽

10.1177/1533033819874773 ◽

2019 ◽

Vol 18 ◽

pp. 153303381987477

Author(s):

Li Q. Zhang ◽

Hua Q. Yang ◽

Su Q. Yang ◽

Ying Wang ◽

Xian J. Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Nude Mice ◽

Cancer Metastasis ◽

Akt Pathway ◽

Migration And Invasion ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Skov3 Cells ◽

Cancer Tissues

Introduction: The mechanism of tumorigenesis and metastasis of ovarian cancer has not yet been elucidated. This study aimed to investigate the role and molecular mechanism of cytosolic nonspecific dipeptidase 2 in tumorigenesis and metastasis. Methods: Cytosolic nonspecific dipeptidase 2 expression in human ovarian cancer tissues and cell lines was assessed with methyl thiazolyl tetrazolium (MTT), clone formation, and transwell assays performed to evaluate the ability of ovarian cancer cells to proliferate and migrate. Nude mice tumor formation experiments were also performed by subcutaneously injecting cells with stable cytosolic nonspecific dipeptidase 2 knockdown and control SKOV3 cells into BALB/c female nude mice to detect changes in PI3K/AKT pathway-related proteins by Western blotting. Results: Cytosolic nonspecific dipeptidase 2 was highly expressed in human ovarian cancer tissues, with its expression associated with pathological data, including ovarian cancer metastasis. A cytosolic nonspecific dipeptidase 2 stable knockdown or ectopic expression ovarian cancer cell model was established and demonstrated that cytosolic nonspecific dipeptidase 2 could promote the proliferation of ovarian cancer cells. Transwell cell migration and invasion assays confirmed that cytosolic nonspecific dipeptidase 2 enhanced cell metastasis in ovarian cancer. Furthermore, in vivo xenograft experiments demonstrated that cytosolic nonspecific dipeptidase 2 can promote the development and progression of ovarian cancer, increasing the expression of phosphorylated PI3K and AKT. Conclusions: Cytosolic nonspecific dipeptidase 2 promotes the occurrence and development of ovarian cancer through the PI3K/AKT signaling pathway.

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Combined chemotherapy and allogeneic human Vγ9Vδ2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells in vivo

OncoImmunology ◽

10.1080/2162402x.2019.1649971 ◽

2019 ◽

Vol 8 (11) ◽

pp. e1649971 ◽

Cited By ~ 2

Author(s):

Noémie Joalland ◽

Laura Lafrance ◽

Thibauld Oullier ◽

Séverine Marionneau-Lambot ◽

Delphine Loussouarn ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

T Lymphocyte ◽

Ovarian Cancer Cells ◽

Combined Chemotherapy

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miR-874-3p mitigates cisplatin resistance through modulating NF-κB/inhibitor of apoptosis protein signaling pathway in epithelial ovarian cancer cells

Molecular and Cellular Biochemistry ◽

10.1007/s11010-021-04271-6 ◽

2021 ◽

Author(s):

Ying Wang ◽

Chenming Yan ◽

Junxia Qi ◽

Chunyan Liu ◽

Juan Yu ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Cisplatin Resistance ◽

Ovarian Cancer Cells ◽

Inhibitor Of Apoptosis ◽

Protein Signaling ◽

Inhibitor Of Apoptosis Protein ◽

Apoptosis Protein

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Knockdown of BRCA2 enhances cisplatin and cisplatin-induced autophagy in ovarian cancer cells

Endocrine Related Cancer ◽

10.1530/erc-17-0261 ◽

2018 ◽

Vol 25 (1) ◽

pp. 69-82 ◽

Cited By ~ 16

Author(s):

Biao Wan ◽

Leheyi Dai ◽

Li Wang ◽

Ying Zhang ◽

Hong Huang ◽

...

Keyword(s):

Ovarian Cancer ◽

Median Time ◽

Progression Free Survival ◽

Ovarian Cancer Cells ◽

Intact Cells ◽

Ovarian Cancer Cell Lines ◽

Tumor Tissues ◽

Cancer Tissues

Clinical implications of the BRCA2 expression level on treatments of ovarian cancer are controversial. Here, we demonstrated that platinum-resistant cancer had a higher percentage of high BRCA2 level (87.5% vs 43.6%, P = 0.001), and that patients with a low BRCA2 level in cancer tissues had longer progression-free survival (with a median time of 28.0 vs 12.0 months, P < 0.001) and platinum-free duration (with a median time of 19.0 vs 5.0 months, P < 0.001) compared with those with a high BRCA2 level. In human ovarian cancer cell lines CAOV-3 and ES-2, cisplatin induced an upregulation of the RAD51 protein, which was inhibited after silencing BRCA2; silencing BRCA2 enhanced the action of cisplatin in vitro and in vivo. Knockdown of BRCA2 promoted cisplatin-induced autophagy. Interestingly, the autophagy blocker chloroquine enhanced cisplatin in BRCA2-silenced cells accompanied by an increase in apoptotic cells, which did not occur in BRCA2-intact cells; chloroquine enhanced the efficacy of cisplatin against BRCA2-silenced CAOV-3 tumors in vivo, with an increase in LC3-II level in tumor tissues. Sensitization of cisplatin was also observed in BRCA2-silenced CAOV-3 cells after inhibiting ATG7, confirming that chloroquine modulated the sensitivity via the autophagy pathway. These data suggest that a low BRCA2 level can predict better platinum sensitivity and prognosis, and that the modulation of autophagy can be a chemosensitizer for certain cancers.

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HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation

Cellular Oncology ◽

10.1007/s13402-016-0308-2 ◽

2016 ◽

Vol 40 (2) ◽

pp. 133-144 ◽

Cited By ~ 29

Author(s):

Suresh Bugide ◽

Vijay Kumar Gonugunta ◽

Vasudevarao Penugurti ◽

Vijaya Lakshmi Malisetty ◽

Ratna K. Vadlamudi ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Epithelial Mesenchymal Transition ◽

Akt Pathway ◽

Ovarian Cancer Cells ◽

Mesenchymal Transition ◽

Pathway Activation

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Knockdown of Rab25 expression by RNAi inhibits growth of human epithelial ovarian cancer cells in vitro and in vivo

Pathology ◽

10.1080/00313020601024037 ◽

2006 ◽

Vol 38 (6) ◽

pp. 561-567 ◽

Cited By ~ 34

Author(s):

Fan Yang ◽

Xin Xiao-Yan ◽

Chen Bi-Liang ◽

Ma Xiangdong

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Ovarian Cancer Cells

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Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Cancers ◽

10.3390/cancers12020296 ◽

2020 ◽

Vol 12 (2) ◽

pp. 296 ◽

Cited By ~ 3

Author(s):

Martyna Pakuła ◽

Ewa Mały ◽

Paweł Uruski ◽

Anna Witucka ◽

Małgorzata Bogucka ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Malignant Ascites ◽

Cyclin B1 ◽

Ovarian Cancer Cells ◽

Independent Manner ◽

Primary Epithelial Ovarian Cancer ◽

Stress Dependent

Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA-β-Gal, γ-H2A.X), growth-arrest in the G1 phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-κB, and STAT3 pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, HGF, and TGF-β1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored.

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