OVCAR-3 Spheroid-Derived Cells Display Distinct Metabolic Profiles

Vermeersch, Kathleen A.; Wang, Limin; Mezencev, Roman; McDonald, John F.; Styczynski, Mark P.

doi:10.1371/journal.pone.0118262

Cited by 31 publications

(30 citation statements)

References 64 publications

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“…These subpopulations of cancer cells are believed to have CSC characteristics such as self-renewal ability and unlimited differentiation. Our group and other investigators have demonstrated that the spheroids of established ovarian cancer cell lines and transplanted human ovarian cancer possess the characteristics of OVCSLCs (3,4,(11)(12)(13)(14). In the present study, we also identified the characteristics of OVCSLCs in spheroids obtained from SKOV3 cells.…”

Section: Resultssupporting

confidence: 61%

Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity

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Cao

et al. 2017

Oncology Reports

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Abstract. Cancer stem cells (CSCs) have central functions in cancer formation and development. Aberrant expression of AKT, ERK and NF-κB signaling pathways have been reported in several types of CSCs. Phytochemicals from dietary compounds possess anti-CSC properties, and have been characterized as promising therapeutic agents for the prevention and treatment of many types of cancers. We previously showed that the newly synthesized genistein derivative, 7-difluoromethoxyl-5,4'-di-n-octylygenistein (DFOG), can inhibit the self-renewal ability of ovarian cancer stem cells (OVCSLCs). In the present study, we further assessed whether various signaling pathways are regulated by DFOG. We found that spheroids derived from the SKOV3 cell line possessed OVCSLC properties and DFOG efficiently inhibited the stemness of the OVCSLCs. In addition, the suppression of spheroid and colony formation by DFOG was associated with inhibition of AKT and ERK1/2 protein phosphorylation, and NF-κB activity in OVCSLCs from the SKOV3 cells. Importantly, DFOG inhibited the oncogenicity of the OVCSLCs by activation of FoxO3a and/or inactivation of FoxM1 by the targeting of multiple pro-survival (AKT and ERK1/2) and proinflammatory (NF-κB) pathways, providing a new avenue for the treatment of ovarian carcinoma in humans.

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Section: Resultssupporting

confidence: 61%

Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity

Ning

Cao

et al. 2017

Oncology Reports

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“…One of the experimental approaches for obtaining CSC-like properties in cells is to culture cancer cells in suspension, resulting in spheroid-shaped cells [6–8]. Indeed, a previous study has suggested that metabolic profiles in spheroid-derived cells from ovarian serous adenocarcinoma were different from those in cancer cells that were cultured in adherent plates [8].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, a previous study has suggested that metabolic profiles in spheroid-derived cells from ovarian serous adenocarcinoma were different from those in cancer cells that were cultured in adherent plates [8]. The significance and implications of this difference were not fully discussed.…”

Section: Introductionmentioning

confidence: 99%

Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle

et al. 2016

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The Warburg effect is a metabolic hallmark of cancer cells; cancer cells, unlike normal cells, exclusively activate glycolysis, even in the presence of enough oxygen. On the other hand, intratumoral heterogeneity is currently of interest in cancer research, including that involving cancer stem cells (CSCs). In the present study, we attempted to gain an understanding of metabolism in CSCs that is distinct from that in non-CSCs. After forming spheroids from the OVTOKO (ovarian clear cell adenocarcinoma) and SiHa (cervical squamous cell carcinoma) cell lines, the metabolites of these cells were compared with the metabolites of cancer cells that were cultured in adherent plates. A principle components analysis clearly divided their metabolic features. Amino acids that participate in tricarboxylic acid (TCA) cycle reactions, such as serine and glutamine, were significantly increased in the spheroids. Indeed, spheroids from each cell line contained more total adenylates than did their corresponding cells in adherent cultures. This study demonstrated that cancer metabolism is not limited to aerobic glycolysis (i.e. the Warburg effect), but is flexible and context-dependent. In addition, activation of TCA cycles was suggested to be a metabolic feature of CSCs that was distinct from non-CSCs. The amino acid metabolic pathways discussed here are already considered as targets for cancer therapy, and they are additionally proposed as potential targets for CSC treatment.

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“…(Thus, no further normalization of measured analyte peak areas to indicators of cell number was necessary; normalization in all figures is only the result of post-processing and variable scaling.) Residues were derivatized as previously described 22–24 . Briefly, 5 μL of 40 mg/mL O -methylhydroxylamine hydrochloride (MP Biomedicals, Santa Ana, CA) in pyridine was added to the dried sample and shaken at 1400 rpm for 90 min at 30°C.…”

Section: Experimental Methodsmentioning

confidence: 99%

“…Data analysis was performed as previously described 23, 24 . Briefly, instrument output was first analyzed with ChromaTOF (LECO, St. Joseph, MI) to determine baseline, peak area, and peak identities.…”

Section: Experimental Methodsmentioning

confidence: 99%

Metabolomics identifies the intersection of phosphoethanolamine with menaquinone-triggered apoptosis in an in vitro model of leukemia

et al. 2015

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Altered metabolism is increasingly acknowledged as an important aspect of cancer, and thus serves as a potentially fertile area for the identification of therapeutic targets or leads. Our recent work using transcriptional data to predict metabolite levels in cancer cells led to preliminary evidence of the antiproliferative role of menaquinone (Vitamin K2) in the Jurkat cell line model of acute lymphoblastic leukemia. However, nothing is known about the direct metabolic impacts of menaquinone in cancer, which could provide insights into its mechanism of action. Here, we used metabolomics to investigate the process by which menaquinone exerts antiproliferative activity on Jurkat cells. We first validated the dose-dependent, semi-selective, pro-apoptotic activity of menaquinone treatment on Jurkat cells relative to non-cancerous lymphoblasts. We then used mass spectrometry-based metabolomics to identify systems-scale changes in metabolic dynamics that are distinct from changes induced in non-cancerous cells or by other chemotherapeutics. One of the most significantly affected metabolites was phosphoethanolamine, which exhibited a two-fold increase in menaquinone-treated Jurkat cells compared to vehicle-treated cells at 24 h, growing to a five-fold increase at 72 h. Phosphoethanolamine elevation was observed prior to the induction of apoptosis, and was not observed in menaquinone-treated lymphoblasts or chemotherapeutic-treated Jurkat cells. We also validated the link between menaquinone and phosphoethanolamine in an ovarian cancer cell line, suggesting potentially broad applicability of their relationship. This metabolomics-based work is the first detailed characterization of the metabolic impacts of menaquinone treatment and the first identified link between phosphoethanolamine and menaquinone-induced apoptosis.

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OVCAR-3 Spheroid-Derived Cells Display Distinct Metabolic Profiles

Cited by 31 publications

References 64 publications

Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity

Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity

Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle

Metabolomics identifies the intersection of phosphoethanolamine with menaquinone-triggered apoptosis in an in vitro model of leukemia

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