Endometrial cancer cells exhibit high expression of p110β and its selective inhibition induces variable responses on PI3K signaling, cell survival and proliferation

Karlsson, Thomas; Krakstad, Camilla; Tangen, Ingvild L.; Høivik, Erling A.; Pollock, Pamela M.; Salvesen, Helga B.; Lewis, Aurélia E.

doi:10.18632/oncotarget.13989

Cited by 13 publications

(23 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The number of samples per grade were as follows: G1= 267, G2= 210, G3= 237.The levels of PtdIns(3,4,5)P 3 are increased in nuclei of EC cells in a p110β-dependent mannerWe next determined if the presence of p110β in the nucleus correlated with nuclear PI3K pathway activity by first assessing the presence of active p-S473-AKT. As shown inFigure 2A, the cytoplasmic and nuclear levels of p-S473-AKT were low in EM, KLE, EFE-184 and MFE-280 cells, while high levels were observed in PTEN-deficient cells, MFE-296, MFE-319, RL95-2 and Ishikawa cells, consistent with our previous study using total cell extracts in the same cells[47]. Interestingly, high nuclear p-S473-AKT levels were inversely correlated with low levels of p85β (Figure 1A).…”

supporting

confidence: 90%

“…PtdIns (3,4,5)P3 and p110β levels, have significantly increased pre-rRNA transcription. The proliferation of these cells was shown to be at least partly dependent upon the activity of p110β [47]. This would suggest that an increase in ribosome production will help increase cell proliferation and subsequently cancer progression.…”

Section: Discussionmentioning

confidence: 96%

“…PIK3CB mRNA levels were found to be elevated in endometrial tumours compared to normal tissue in a few patient samples [46]. In a recent study, we have shown that the p110β protein levels are elevated in EC cell lines and that mRNA levels are increased in grade 1 endometrioid endometrial lesions compared to complex hyperplasias [47]. We have recently reported the presence of p110β and of its product PtdIns (3,4,5)P3 in the nucleolus of the breast cancer cell line AU565 [29].…”

Section: Introductionmentioning

confidence: 93%

See 2 more Smart Citations

Nuclear upregulation of PI3K p110β correlates with increased rRNA transcription in endometrial cancer cells

Gavgani

Karlsson

Tangen

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Genes encoding for components of the phosphoinositide 3-kinase (PI3K) pathway are frequently mutated in cancer, including inactivating mutations of PTEN and activating mutations of PIK3CA, encoding the PI3K catalytic subunit p110α. PIK3CB, encoding p110β, is rarely mutated, but can contribute to tumourigenesis in some PTEN-deficient tumours. The underlying molecular mechanisms are however poorly understood. By analysing cell lines and annotated clinical samples, we have previously found that p110β is highly expressed in endometrial cancer (EC) cell lines and that PIK3CB mRNA levels increase early in primary tumours correlating with lower survival. Selective inhibition of p110α and p110β led to different effects on cell signalling and cell function, p110α activity being correlated to cell survival in PIK3CA mutant cells and p110β with cell proliferation in PTEN-deficient cells. To understand the mechanisms governing the differential roles of these isoforms, we assessed their sub-cellular localisation. p110α was cytoplasmic whereas p110β was both cytoplasmic and nuclear with increased levels in both compartments in cancer cells. Immunohistochemistry of p110β in clinically annotated patient tumour sections revealed high nuclear/cytoplasmic staining ratio, which correlated significantly with higher grades. Consistently, the presence of high levels of p110β in the nuclei of EC cells, correlated with high levels of its product phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) in the nucleus. Using immunofluorescence labelling, we observed both p110β and PtdIns(3,4,5)P3 in the nucleoli of EC cell lines. The production of nucleolar PtdIns(3,4,5)P3 was dependent upon p110β activity.EC cells with high levels of nuclear PtdIns(3,4,5)P3 and p110β showed elevated nucleolar activity as assessed by the increase in 47S pre-rRNA transcriptional levels in a p110βdependent manner. Altogether, these results present a nucleolar role for the PI3K pathway that may contribute to tumour progression in endometrial cancer.

show abstract

supporting

confidence: 90%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 93%

See 1 more Smart Citation

Nuclear upregulation of PI3K p110β correlates with increased rRNA transcription in endometrial cancer cells

Gavgani

Karlsson

Tangen

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Endometrial cancer is characterized by genetic aberration including activation of mTOR and loss of PTEN, a tumor suppressor gene which regulates the cell cycle and survival through its signal transduction pathway and whose loss enhances stimulation of the mTOR pathway [118,119].…”

Section: Metforminmentioning

confidence: 99%

Linking type 2 diabetes and gynecological cancer: an introductory overview

Anastasi

Filardi

Tartaglione

et al. 2018

Clinical Chemistry and Laboratory Medicine (CCLM)

View full text Add to dashboard Cite

Type 2 diabetes (T2D) is a chronic disease with a growing prevalence and a leading cause of death in many countries. Several epidemiological studies observed an association between T2D and increased risk of many types of cancer, such as gynecologic neoplasms (endometrial, cervical, ovarian and vulvar cancer). Insulin resistance, chronic inflammation and high free ovarian steroid hormones are considered the possible mechanisms behind this complex relationship. A higher risk of endometrial cancer was observed in T2D, even though this association largely attenuated after adjusting for obesity. A clear relationship between the incidence of cervical cancer (CC) and T2D has still not be determined; however T2D might have an impact on prognosis in patients with CC. To date, studies on the association between T2D and ovarian cancer (OC) are limited. The effect of pre-existing diabetes on cancer-specific mortality has been evaluated in several studies, with less clear results. Other epidemiological and experimental studies focused on the potential role of diabetes medications, mainly metformin, in cancer development in women. The correct understanding of the link between T2D and gynecologic cancer risk and mortality is currently imperative to possibly modify screening and diagnostic-therapeutic protocols in the future.

show abstract

“…This strategy had the advantage of not disrupting the expression and stoichiometry of the catalytic/regulatory PI3K complex. In cell studies, p110α was shown to have a role in cell survival and p110β in DNA synthesis or cell proliferation [41,42,43,44]. Their distinct cellular localisation can be a feature explaining their different cellular roles.…”

Section: The Phosphoinositide 3-kinase Pathwaymentioning

confidence: 99%

Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer

Gavgani

Arnesen

Jacobsen

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

The phosphoinositide 3-kinase (PI3K) signalling pathway is highly dysregulated in cancer, leading to elevated PI3K signalling and altered cellular processes that contribute to tumour development. The pathway is normally orchestrated by class I PI3K enzymes and negatively regulated by the phosphatase and tensin homologue, PTEN. Endometrial carcinomas harbour frequent alterations in components of the pathway, including changes in gene copy number and mutations, in particular in the oncogene PIK3CA, the gene encoding the PI3K catalytic subunit p110α, and the tumour suppressor PTEN. PIK3CB, encoding the other ubiquitously expressed class I isoform p110β, is less frequently altered but the few mutations identified to date are oncogenic. This isoform has received more research interest in recent years, particularly since PTEN-deficient tumours were found to be reliant on p110β activity to sustain transformation. In this review, we describe the current understanding of the common and distinct biochemical properties of the p110α and p110β isoforms, summarise their mutations and highlight how they are targeted in clinical trials in endometrial cancer.

show abstract

Endometrial cancer cells exhibit high expression of p110β and its selective inhibition induces variable responses on PI3K signaling, cell survival and proliferation

Cited by 13 publications

References 66 publications

Nuclear upregulation of PI3K p110β correlates with increased rRNA transcription in endometrial cancer cells

Nuclear upregulation of PI3K p110β correlates with increased rRNA transcription in endometrial cancer cells

Linking type 2 diabetes and gynecological cancer: an introductory overview

Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer

Contact Info

Product

Resources

About