Autophagy Is Indispensable for the Self‐Renewal and Quiescence of Ovarian Cancer Spheroid Cells with Stem Cell‐Like Properties

Wang, Qian; Bu, Shi; Xin, Dedong; Li, Boning; Wang, Lan; Lai, Dongmei

doi:10.1155/2018/7010472

Cited by 26 publications

(25 citation statements)

References 55 publications

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“…We first examined the viability of OCCC cell lines in suspension culture over time and made the unexpected observation that several lines (RMG-I, TOV-21G, KOC-7c, ES-2) proliferate in suspension culture. This was surprising as previous reports have characterized EOC and other cancer cell spheroids as quiescent and non-proliferative [33,[71][72][73][74]. We found most OCCC lines showed a dramatic increase in sensitivity to AZD-8055 as measured by cell viability when maintained in spheroid culture.…”

Section: Mtor Pathway Inhibition and Carboplatin Treatmentcontrasting

confidence: 73%

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

Kolendowski

Valdes

Hirte

et al. 2020

Cells

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Ovarian clear cell carcinoma (OCCC) is a rare subtype of gynecological cancer for which well-characterized and authenticated model systems are scarce. We provide an extensive characterization of ‘105C’, a cell line generated from an adenocarcinoma of the clear cell histotype using targeted next-generation sequencing, cytogenetic microarrays, along with analyses of AKT/mTOR signaling. We report that that the 105C cell line is a bona fide OCCC cell line, carrying PIK3CA, PTEN, and ARID1A gene mutations, consistent with OCCC, yet maintain a stable genome as reflected by low copy number variation. Unlike KOC-7c, TOV-21G, and RMG-V OCCC lines also mutated for the above genes, the 105C cells do not carry mutations in mismatch repair genes. Importantly, we show that 105C cells exhibit greater resistance to mTOR inhibition and carboplatin treatment compared to 9 other OCCC cell lines in 3D spheroid cultures. This resistance may be attributed to 105C cells remaining dormant in suspension culture which surprisingly, contrasts with several other OCCC lines which continue to proliferate in long-term suspension culture. 105C cells survive xenotransplantation but do not proliferate and metastasize. Collectively, we show that the 105C OCCC cell line exhibits unique properties useful for the pre-clinical investigation of OCCC pathobiology.

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Section: Mtor Pathway Inhibition and Carboplatin Treatmentcontrasting

confidence: 73%

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

Kolendowski

Valdes

Hirte

et al. 2020

Cells

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“…Under environmental stresses, the induction of autophagy seems to be important in the regulation of stem cell activation [9]. For example, autophagy regulates the entry of glioblastoma cells and ovarian cancer spheroid cells into the quiescent state [10, 28]. However, the detailed mechanism of autophagy in the regulation of quiescence remains to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Autophagy mediates serum starvation-induced quiescence in nucleus pulposus stem cells by the regulation of P27

Sun

et al. 2019

Stem Cell Res Ther

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Background Adult stem cells exist in a quiescent state (G0) within the in vivo niche; the loss of quiescence often leads to a decrease in the number and function of adult stem cells, impairing tissue regeneration and repair. Endogenous repair by nucleus pulposus-derived stem cells has recently shown promising regenerative potential for the treatment of intervertebral disc degeneration (IDD). However, the number and function of nucleus pulposus stem cells (NPSCs) declined throughout the process of IDD. This effect may have a specific relationship with quiescence. However, the biology of the quiescent NPSCs has not been reported. Methods First, we established an in vitro model for NPSC quiescence with serum starvation. The induction of G0 was confirmed by flow cytometry analyses of dual staining with Hoechst 33342 and Pyronin Y, immunofluorescent staining with Ki67 and Western blot analysis of P27 expression. NPSCs were cultured under serum starvation conditions for a long time period (21 days). To examine the functional phenotype of quiescent NPSCs, the cells were reactivated with 10% serum and differentiated into osteogenic and chondrogenic lineages in vitro. The number of colony-forming units was also estimated. To elucidate the role of autophagy in the quiescence of NPSCs, we activated and inhibited autophagy in starved cells with rapamycin and chloroquine, respectively. Then, the expression of P27 was evaluated by Western blot analysis, and the immunofluorescence of Ki67 was assessed. Finally, we assessed the role of P27 siRNA in NPSC quiescence by flow cytometry analyses and 5-ethynyl-20-deoxyuridine incorporation assays under normal and serum-starved conditions. Results NPSC quiescence was induced by 48 h of serum starvation, and they maintained quiescence for up to 21 days. Upon reactivation with serum, the quiescent NPSCs re-entered the cell cycle and exhibited enhanced clonogenic self-renewal, osteogenic differentiation and chondrogenic differentiation potentials compared to control NPSCs under normal culture conditions. We also found that autophagy underlay serum starvation-induced NPSC quiescence. Further study demonstrated that autophagy mediated the quiescence of NPSCs by regulating P27. Conclusions Serum starvation efficiently induces quiescence in NPSCs. Quiescent NPSCs maintain stem cell properties. Our study reveals that autophagy plays a role in maintaining NPSC quiescence and that autophagy mediates the quiescence of NPSCs by regulating P27. We conclude that the induction of quiescence in cultured NPSCs provides a useful model for the analysis of mechanisms that might be relevant to the biology of NPSCs in vivo.

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“…UBE2L6 depletion can activate autophagy and regulate the chemosensitivity of esophageal cancer cells [33]. Serving as either oncogenic or anti-tumor regulator, autophagy is widely implicated in regulation of stem maintenance, proliferation, invasion, metastasis, and therapy resistance of OC [27,28,35]. Here, we validated that UBE2T inhibition could promote autophagy, subsequently suppress the malignant characteristics of OC cells via constraining AKT/mTOR.…”

Section: Discussionmentioning

confidence: 58%

UBE2T is upregulated, predicts poor prognosis, and promotes cell proliferation and invasion via inhibiting autophagy in ovarian cancer

Huang

Xiao

et al. 2020

Preprint

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Background: Aberrant upregulation and oncogenic roles of UBE2T have been revealed in several cancers. However, the expression, clinical significance, and functions of UBE2T has not been explored in ovarian cancer (OC).Methods: In this study, the mRNA and protein expression of UBE2T in OC were detected via analyzing the online databases and immunohistochemical staining. Moreover, relations of UBE2T expression with clincopathological features and prognosis OC patients were further analyzed. Besides, the effects of UBE2T knockdown on growth, proliferation, and invasion of OC cells were investigated by CCK-8, plate clone formation, and Transwell assays. Finally, the underlying mechanism of UBE2T associated functions in OC was analyzed.Results: The results indicated that UBE2T was significantly upregulated in OC tissues. UBE2T expression was notably correlated with clinical features such as primary T stage, TNM stage in OC patients. UBE2T, acting as an independent prognostic indicator, was inversely associated with prognosis of OC patients. UBE2T knockdown remarkably suppressed the growth, proliferation, and invasion of OC cells indicating by impaired cell viability, less cell clones and invasive cells. Mechanistically, the oncogenic roles of UBE2T was exerted by inhibiting autophagy via maintaining AKT/mTOR activity in OC.Conclusion: Collectively, our findings confirm UBE2T upregulation predicts poor prognosis and promotes malignant progression via suppressing autophagy in OC, suggesting the promising values of UBE2T both in diagnosis and treatment of OC.

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Autophagy Is Indispensable for the Self‐Renewal and Quiescence of Ovarian Cancer Spheroid Cells with Stem Cell‐Like Properties

Cited by 26 publications

References 55 publications

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

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

Autophagy mediates serum starvation-induced quiescence in nucleus pulposus stem cells by the regulation of P27

UBE2T is upregulated, predicts poor prognosis, and promotes cell proliferation and invasion via inhibiting autophagy in ovarian cancer

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