Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β 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 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.

Structural Perturbations due to Mutation (H1047R) in Phosphoinositide-3-kinase (PI3Kα) and Its Involvement in Oncogenesis: An in Silico Insight

“…Class IA has p110 (α/β/δ, which are gene products of PIK3CA/PIK3CB/PIK3CD, respectively) as the catalytic subunit that interacts with p85 which acts as the regulatory subunit. 4−7,12…”

“…2,21 The most common mutations being H1047R of the kinase domain and E542K and E545K of the helical domain. 4,21 Kinase domain mutation does not require the involvement of the RBD with the membrane protein RAS but depends on p85α for activation. 11,39 H1047R mutation causes structural transformations in the kinase domain which increases the membrane association of PI3Kα, thereby increasing the lipid kinase activity.…”

Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence

“… 172 – 174 As for gynecological cancers, this pathway is overactivated in OC (~70%), 175 – 177 as well as EC and CC. 178 – 180 In EC, the mutation rates of PI3K and PTEN were high, especially in the POLE subgroup. 20 In vitro model of CC, mTOR inhibitors markedly reduced the expression level of HPV E7 protein, inducing apoptosis.…”

miR-155 as an Important Regulator of Multiple Sclerosis Pathogenesis. A Review

“…It has been found that miR-155 is one of the most crucial miRNAs in MS as it regulates MS risk genes PIK3R1 and PIK3CA and correlates with severity of the disease [49]. These genes encode p85-α and p110-α proteins, members of phosphoinositide 3-kinase (PI3K) family [66,67]. Abnormalities in PI3K contribute to, e.g., cancer development, neurological and immunological dysfunctions, dendritic cells functioning, EAE pathogenesis and demyelination in MS [49].…”