The Gene Expression Status of the PI3K/AKT/mTOR Pathway in Gastric Cancer Tissues and Cell Lines

Abstract

The PI3K/AKT/mTOR pathway plays a crucial role in the regulation of multiple cellular functions including cell growth, proliferation, metabolism and angiogenesis. Emerging evidence has shown that deregulation of this pathway has a role promoting gastric cancer (GC). The aim was to assess the expression of genes involved in this pathway by qPCR in 23 tumor and 23 non-tumor gastric mucosa samples from advanced GC patients, and in AGS, MKN28 and MKN45 gastric cancer cell lines. Results showed a slight overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1, EIF4EBP1 and EIF4E genes, and a slightly decreased PTEN and TSC1 expression. In AGS, MKN28 and MKN45 cells a significant gene overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1 and EIF4E, and a significant repression of PTEN gene expression were observed. Immunoblotting showed that PI3K-β, AKT, p-AKT, PTEN, mTOR, p-mTOR, P70S6K1, p-P70S6K1, 4E-BP1, p-4E-BP1, eIF4E and p-eIF4E proteins were present in cell lines at different levels, confirming activation of this pathway in vitro. This is the first time this extensive panel of 9 genes within PI3K/AKT/mTOR pathway has been studied in GC to clarify the biological role of this pathway in GC and develop new strategies for this malignancy.

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

“…P27kip1 belongs to the CDK inhibitor protein family and negatively regulates the cell cycle; it inhibits the activity of CDK, leading to cell cycle arrest and blockage of cell proliferation. AKT inhibits the cell cycle blockade by phosphorylating P27kip1 and accelerates cell proliferation and differentiation [105]. Additionally, mTOR helps to regulate the synthesis of biological macromolecules such as proteins, nucleotides, and lipids, thus providing the materials necessary for cancer cell growth [106].…”

Phosphorylated Mammalian Target of Rapamycin p-mTOR Is a Favorable Prognostic Factor than mTOR in Gastric Cancer

“…Riquelme et al . [33] found that rapamycin treatment did not significantly alter the protein expression of total mTOR in several types of cell lines. However, rapamycin significantly decreased the phosphorylation of both mTOR and its downstream effectors, such as p70S6K1 and 4E-BP1.…”

Gastric cancer management: Kinases as a target therapy

“…The landmark TCGA study examined 295 gastric cancer tumours using six different molecular analysis platforms encompassing DNA, RNA and protein assays and proposed a novel molecular characterization defined by four genomic subtypes: Epstein–Barr virus (EBV)‐positive, microsatellite unstable (MSI), genomically stable (GS) and chromosomal instability (CIN) . EBV‐positive tumours, which represent 9%‐10% of gastric adenocarcinomas, harbour high levels of non‐silent PI3KCA mutations (80%), extreme DNA hypermethylation, mutations in PTEN, SMADA, CDKN2A, ARIDA (55%) and BCOR (23%) and amplification of JAK2, ERBB2, PD‐L1 and PD‐L, suggesting that PI3K, JAK2 and immune checkpoint inhibitors could constitute valuable therapeutic options for the treatment of this tumour subtype …”

“…Three types of PI3K inhibitors have been developed to target this prominent signalling cascade, including pan‐class I inhibitors active against p110 isoforms, isoform‐specific PI3K inhibitors and dual PI3K/mTOR inhibitors, which target both PI3K and mTOR kinases . Recent research has shown that PI3KCA, PI3KCB, AKT1 and mTOR are overexpressed in GC cell lines and that the PI3K/AKT/mTOR pathway is activated in up to 60% of GC patients, corroborating the therapeutic susceptibility of this pathway . Consequently, various clinical trials evaluating the efficacy of AKT, PI3K and mTOR inhibitors against GC are underway.…”

“…8 EBV-positive tumours, which represent 9%-10% of gastric adenocarcinomas, harbour high levels of non-silent PI3KCA mutations (80%), extreme DNA hypermethylation, mutations in PTEN, SMADA, CDKN2A, ARIDA (55%) and BCOR (23%) and amplification of JAK2, ERBB2, PD-L1 and PD-L, suggesting that PI3K, JAK2 and immune checkpoint inhibitors could constitute valuable therapeutic options for the treatment of this tumour subtype. [8][9][10][11][12] Microsatellite unstable tumours (22%) are prevalent in women and older patients, exhibit elevated levels of microsatellite instability without major chromosomal abnormalities and strongly correlate with MLH1 promoter hypermethylation as well as recurrent mutations in PIK3CA, ERBB3, ERBB2 and epidermal growth factor receptor (EGFR) but lack targetable amplifications. 8,9,12,13 GS tumours (20%), associated with diffuse-type adenocarcinomas, are diagnosed in younger patients and enriched with recurrent CDH1 (37%), RHOA (15%) and inactivating ARID1A mutations.…”