Characterization of Mutational Status, Spheroid Formation, and Drug Response of a New Genomically-Stable Human Ovarian Clear Cell Carcinoma Cell Line, 105C

Kolendowski, Bart; Valdes, Yudith Ramos; Hirte, Hal W.; Itamochi, Hiroaki; Lee, Won–Jae; Carey, Mark; Shepherd, Trevor G.; DiMattia, Gabriel E.

doi:10.3390/cells9112408

Cited by 5 publications

(4 citation statements)

References 84 publications

(111 reference statements)

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“…The shift from adherent to spheroid cells during EOC metastasis has previously been reported to be AKT-dependent [ 2 , 38 , 39 , 40 ], and spheroid cells are characterized by low S473 phosphorylation levels on AKT [ 2 , 38 ]. We previously showed that T308 phosphorylation is the primary determinant for AKT1 activity [ 6 , 7 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

miRNA-Dependent Regulation of AKT1 Phosphorylation

Frederick

Siddika

Zhang

et al. 2022

Cells

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The phosphoinositide-3-kinase (PI3K)/AKT pathway regulates cell survival and is over-activated in most human cancers, including ovarian cancer. Following growth factor stimulation, AKT1 is activated by phosphorylation at T308 and S473. Disruption of the AKT1 signaling pathway is sufficient to inhibit the epithelial-mesenchymal transition in epithelial ovarian cancer (EOC) cells. In metastatic disease, adherent EOC cells transition to a dormant spheroid state, characterized previously by low S473 phosphorylation in AKT1. We confirmed this finding and observed that T308 phosphorylation was yet further reduced in EOC spheroids and that the transition from adherent to spheroid growth is accompanied by significantly increased levels of let-7 miRNAs. We then used mechanistic studies to investigate the impact of let-7 miRNAs on AKT1 phosphorylation status and activity in cells. In growth factor-stimulated HEK 293T cells supplemented with let-7a, we found increased phosphorylation of AKT1 at T308, decreased phosphorylation at S473, and enhanced downstream AKT1 substrate GSK-3β phosphorylation. Let-7b and let-7g also deregulated AKT signaling by rendering AKT1 insensitive to growth factor simulation. We uncovered let-7a-dependent deregulation of PI3K pathway components, including PI3KC2A, PDK1, and RICTOR, that govern AKT1 phosphorylation and activity. Together, our data show a new role for miRNAs in regulating AKT signaling.

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Section: Discussionmentioning

confidence: 99%

miRNA-Dependent Regulation of AKT1 Phosphorylation

Frederick

Siddika

Zhang

et al. 2022

Cells

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“…ES-2 used in a previous report [32] showed mutations only in NOTCH3, similar to RMG-I. In OCCC, a combination of mutations in ARID1A and PIK3CA is more frequent [40] because metformin was found to be effective in both OVISE, which has these mutations, and RMG-I, which does not. This highlights the possibility of using metformin as an antitumor drug targeting OCCC.…”

Section: Discussionmentioning

confidence: 79%

“…The strength of this study lies in its demonstration of the antitumor effects of metformin in several OCCC cell lines with different genetic mutation patterns. The OCCC cell lines used in this study were tested for genetic mutations as described by Kashiyama et al and Kolendowski et al [39,40]. To summarize the two reports, RMG-I showed mutations only in NOTCH3, OVISE had mutations in ARIDA and PIK3CA.…”

Section: Discussionmentioning

confidence: 99%

Assessing the antitumor effects of metformin on ovarian clear cell carcinoma

Takemori,

Morisada,

Osaka

et al. 2024

Preprint

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Developing novel therapies that outperform the existing chemotherapeutic treatments is required for treatment-resistant ovarian clear cell carcinoma. We investigated the antitumor effect of metformin on ovarian clear cell carcinoma, enhancement of the antitumor effect by its combination with chemotherapy, and its molecular regulatory mechanism. First, we evaluated the viability of ovarian clear cell carcinoma lines using the water-soluble tetrazolium-1 assay and found that metformin suppressed cell viability. Cell viability was significantly suppressed by co-treatment with cisplatin and metformin. In contrast, co-treatment with paclitaxel and metformin showed no significant difference in viability compared with the group without metformin. Western blot analysis showed increased phosphorylation of AMP-activated protein kinase and suppressed phosphorylation of the mammalian target of rapamycin. Flow cytometry analysis revealed a significant increase in the rate of apoptosis in the metformin-treated group and rate of cell cycle arrest at the G2/M phase. These results indicated that metformin may be effective against cultured ovarian clear cell carcinoma cells, particularly in combination with cisplatin.

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“…According to the comprehensive list of OCCC cell lines provided by Franklin et al [ 12 ] and to the establishment of the 105C cell line [ 13 ], 29 OCCC cell lines have been established so far and some of them are able to generate tight spheroids when cultured in non-adherent conditions [ 14 ]. Nevertheless, most of them have not been extensively characterized and less than half of them have been deposited in cell banks.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of response to treatments and molecular features of tumor-derived organoids versus cell lines and PDX derived from the same ovarian clear cell carcinoma

Thorel,

Morice,

Paysant

et al. 2023

J Exp Clin Cancer Res

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Background In the era of personalized medicine, the establishment of preclinical models of cancer that faithfully recapitulate original tumors is essential to potentially guide clinical decisions. Methods We established 7 models [4 cell lines, 2 Patient-Derived Tumor Organoids (PDTO) and 1 Patient-Derived Xenograft (PDX)], all derived from the same Ovarian Clear Cell Carcinoma (OCCC). To determine the relevance of each of these models, comprehensive characterization was performed based on morphological, histological, and transcriptomic analyses as well as on the evaluation of their response to the treatments received by the patient. These results were compared to the clinical data. Results Only the PDX and PDTO models derived from the patient tumor were able to recapitulate the patient tumor heterogeneity. The patient was refractory to carboplatin, doxorubicin and gemcitabine, while tumor cell lines were sensitive to these treatments. In contrast, PDX and PDTO models displayed resistance to the 3 drugs. The transcriptomic analysis was consistent with these results since the models recapitulating faithfully the clinical response grouped together away from the other classical 2D cell culture models. We next investigated the potential of drugs that have not been used in the patient clinical management and we identified the HDAC inhibitor belinostat as a potential effective treatment based on PDTO response. Conclusions PDX and PDTO appear to be the most relevant models, but only PDTO seem to present all the necessary prerequisites for predictive purposes and could constitute relevant tools for therapeutic decision support in the context of these particularly aggressive cancers refractory to conventional treatments.

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Characterization of Mutational Status, Spheroid Formation, and Drug Response of a New Genomically-Stable Human Ovarian Clear Cell Carcinoma Cell Line, 105C

Cited by 5 publications

References 84 publications

miRNA-Dependent Regulation of AKT1 Phosphorylation

miRNA-Dependent Regulation of AKT1 Phosphorylation

Assessing the antitumor effects of metformin on ovarian clear cell carcinoma

Comparative analysis of response to treatments and molecular features of tumor-derived organoids versus cell lines and PDX derived from the same ovarian clear cell carcinoma

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