AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition

Abstract

Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy.

BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer

“…HCT116 OctaKO cells were kindly provided by the lab of Xu Luo from the University of Nebraska Medical Center (O'Neill et al, 2016). SW948 was maintained as described in Buikhuisen et al, 2021), in 1:1 DMEM/F12 medium containing 15 mM HEPES and 2.5 mM L-glutamine (Gibco) supplemented with 8% fetal bovine serum (Serana) and 50 U/mL of penicillin/streptomycin (Gibco) HCT116 and HCT116 OctaKO cells were maintained in RPMI 1640 medium supplemented with 25 mM HEPES and 2.05 mM L-glutamine (Gibco) supplemented with 8% fetal bovine serum, 1% D-glucose solution plus (Sigma-Aldrich), 1 mM sodium pyruvate (Gibco), and 50 U/mL of penicillin/streptomycin (Buikhuisen et al, 2021). Cultures were tested for mycoplasma contaminations on a monthly basis.…”

miR-3614-3p suppresses cell aggressiveness of human breast cancer by targeting AKT3 and HDAC1 expression

“…Using TargetScan, an online prediction software, AKT3 and HDAC1 were identified as potential target genes of miR-3614-3p, in which AKT, also known as PKB, is vital for maintaining normal cellular function. Concerning its potential role in cancer, previous studies have identified a correlation between tumor development and AKT3 expression (16)(17)(18)(19)(20). Wang et al (21) verified that miR-384 could significantly suppress the proliferation of colorectal cancer by targeting AKT3, and that miRNA-433 targets AKT3, thereby inducing the inhibition of cell proliferation and viability in BC (22).…”

NR2F1-AS1/miR-190a/PHLDB2 Induces the Epithelial–Mesenchymal Transformation Process in Gastric Cancer by Promoting Phosphorylation of AKT3

“…Thus each subtype of AKT has a different biological function (Xue and Hemmings, 2013;Hoxhaj and Manning, 2020). AKT3 has been found to be significantly associated with the EMT process of the thyroid (You et al, 2020), bladder (McNiel andTsichlis, 2017), colorectal (Buikhuisen et al, 2021), and prostate cancer (Galbraith et al, 2021). This suggested that the EMT conversion induced by AKT might be largely dependent on specific AKT molecular subtypes.…”