Dataset Information

Class I Phosphoinositide 3-Kinase PIK3CA/p110? and PIK3CB/p110? Isoforms in Endometrial Cancer.

ABSTRACT: 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 p110?, and the tumour suppressor PTEN. PIK3CB, encoding the other ubiquitously expressed class I isoform p110?, 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 p110? activity to sustain transformation. In this review, we describe the current understanding of the common and distinct biochemical properties of the p110? and p110? isoforms, summarise their mutations and highlight how they are targeted in clinical trials in endometrial cancer.

SUBMITTER: Mazloumi Gavgani F

PROVIDER: S-EPMC6321576 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Mazloumi Gavgani Fatemeh F Smith Arnesen Victoria V Jacobsen Rhîan G RG Krakstad Camilla C Hoivik Erling A EA Lewis Aurélia E AE

International journal of molecular sciences 20181207 12

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 PIK ...[more]

PMID: 30544563

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Project description:BackgroundPI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment.MethodsThe effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP.ResultsBy inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently.ConclusionsThe reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

Dataset Information

Class I Phosphoinositide 3-Kinase PIK3CA/p110? and PIK3CB/p110? Isoforms in Endometrial Cancer.

Publications

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

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