Cell Density-Mediated Pericellular Hypoxia and the Local Dynamic Regulation of VEGF-A Splice Variants in Ovine Ovarian Granulosa Cells1

Marsters, Peter; Alhamdan, Rana; Campbell, Bruce

doi:10.1095/biolreprod.113.113068

Cited by 6 publications

(2 citation statements)

References 43 publications

(64 reference statements)

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“…In HT-29 cells, HIF-1α levels were not significantly increased with an increase in cell density. We hypothesized that the HIF-1α accumulation induced by pericellular hypoxia might already be present in HT-29 cells because of their aggregated form [ 35 ]. The comparatively slight increase in the ROS level in HT-29 cells with the increase in cell density can also be interpreted in this scheme.…”

Section: Discussionmentioning

confidence: 99%

Kv3.1 and Kv3.4, Are Involved in Cancer Cell Migration and Invasion

Song

Park

et al. 2018

IJMS

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Voltage-gated potassium (Kv) channels, including Kv3.1 and Kv3.4, are known as oxygen sensors, and their function in hypoxia has been well investigated. However, the relationship between Kv channels and tumor hypoxia has yet to be investigated. This study demonstrates that Kv3.1 and Kv3.4 are tumor hypoxia-related Kv channels involved in cancer cell migration and invasion. Kv3.1 and Kv3.4 protein expression in A549 and MDA-MB-231 cells increased in a cell density-dependent manner, and the pattern was similar to the expression patterns of hypoxia-inducible factor-1α (HIF-1α) and reactive oxygen species (ROS) according to cell density, whereas Kv3.3 protein expression did not change in A549 cells with an increase in cell density. The Kv3.1 and Kv3.4 blocker blood depressing substance (BDS) did not affect cell proliferation; instead, BDS inhibited cell migration and invasion. We found that BDS inhibited intracellular pH regulation and extracellular signal-regulated kinase (ERK) activation in A549 cells cultured at a high density, potentially resulting in BDS-induced inhibition of cell migration and invasion. Our data suggest that Kv3.1 and Kv3.4 might be new therapeutic targets for cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Kv3.1 and Kv3.4, Are Involved in Cancer Cell Migration and Invasion

Song

Park

et al. 2018

IJMS

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“…However, it is still unclear whether hypoxia is an essential signal during the folliculo-luteal transition [ 11 ]. As for granulosa cells (GC) it was proposed that pericellular hypoxia present under high cell density conditions may induce differentiation [ 12 ]. Likewise, we showed that high cell density induces specific changes of the gene expression and steroid hormone profiles in cultured GC mimicking an early post-LH status of GC differentiation [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Lactate promotes specific differentiation in bovine granulosa cells depending on lactate uptake thus mimicking an early post-LH stage

Baufeld

Vanselow

2018

Reprod Biol Endocrinol

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BackgroundThe LH-induced folliculo-luteal transformation is connected with alterations of the gene expression profile in cells of the granulosa layer. It has been described that hypoxic conditions occur during luteinization, thus favoring the formation of L-lactate within the follicle. Despite being a product of anaerobic respiration, L-lactate has been shown to act as a signaling molecule affecting gene expression in neuronal cells. During the present study, we tested the hypothesis that L-lactate may influence differentiation of follicular granulosa cells (GC).MethodsIn a bovine granulosa cell culture model effects of L- and D-lactate, of increased glucose concentrations and of the lactate transport inhibitor UK5099 were analyzed. Steroid hormone production was analyzed by RIA and the abundance of key transcripts was determined by quantitative real-time RT-PCR.ResultsL-lactate decreased the production of estradiol and significantly affected selected genes of the folliculo-luteal transition as well as genes of the lactate metabolism. CYP19A1, FSHR, LHCGR were down-regulated, whereas RGS2, VNN2, PTX3, LDHA and lactate transporters were up-regulated. These effects could be partly or completely reversed by pre-treatment of the cells with UK5099. The non-metabolized enantiomer D-lactate had even more pronounced effects on gene expression, whereas increased glucose concentrations did not affect transcript abundance.ConclusionsIn summary, our data suggest that L-lactate specifically alters physiological and molecular characteristics of GC. These effects critically depend on L-lactate uptake, but are not triggered by increased energy supply. Further, we could show that L-lactate has a positive feedback on the lactate metabolism. Therefore, we hypothesize that L-lactate acts as a signaling molecule in bovine and possibly other monovular species supporting differentiation during the folliculo-luteal transformation.Electronic supplementary materialThe online version of this article (10.1186/s12958-018-0332-3) contains supplementary material, which is available to authorized users.

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Atypical induction of HIF-1α expression by pericellular Notch1 signaling suffices for the malignancy of glioblastoma multiforme cells

Lee

Kim²,

Chong

et al. 2022

Cell. Mol. Life Sci.

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Contact-based pericellular interactions play important roles in cancer progression via juxtacrine signaling pathways. The present study revealed that hypoxia-inducible factor-1α (HIF-1α), induced even in non-hypoxic conditions by cell-to-cell contact, was a critical cue responsible for the malignant characteristics of glioblastoma multiforme (GBM) cells through Notch1 signaling. Densely cultured GBM cells showed enhanced viability and resistance to temozolomide (TMZ) compared to GBM cells at a low density. Ablating Notch1 signaling by a γ-secretase inhibitor or siRNA transfection resensitized resistant GBM cells to TMZ treatment and decreased their viability under dense culture conditions. The expression of HIF-1α was significantly elevated in highly dense GBM cells even under non-hypoxic conditions. Atypical HIF-1α expression was associated with the Notch1 signaling pathway in both GBM and glioblastoma stem cells (GSC). Proteasomal degradation of HIF-1α was prevented by binding with Notch1 intracellular domain (NICD), which translocated to the nuclei of GBM cells. Silencing Notch1 signaling using a doxycycline-inducible Notch1 RNA-interfering system or treatment with chetomin, a HIF pathway inhibitor, retarded tumor development with a significant anti-cancer effect in a murine U251-xenograft model. Using GBM patient tissue microarray analysis, a significant increase in HIF-1α expression was identified in the group with Notch1 expression compared to the group without Notch1 expression among those with positive HIF-1α expression. Collectively, these findings highlight the critical role of cell-to-cell contact-dependent signaling in GBM progression. They provide a rationale for targeting HIF-1α signaling even in a non-hypoxic microenvironment.

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Cell Density-Mediated Pericellular Hypoxia and the Local Dynamic Regulation of VEGF-A Splice Variants in Ovine Ovarian Granulosa Cells1

Cited by 6 publications

References 43 publications

Kv3.1 and Kv3.4, Are Involved in Cancer Cell Migration and Invasion

Kv3.1 and Kv3.4, Are Involved in Cancer Cell Migration and Invasion

Lactate promotes specific differentiation in bovine granulosa cells depending on lactate uptake thus mimicking an early post-LH stage

Atypical induction of HIF-1α expression by pericellular Notch1 signaling suffices for the malignancy of glioblastoma multiforme cells

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