Membrane metallo‐endopeptidase mediates cellular senescence induced by oncogenic PIK3CA^H1047R accompanied with pro‐tumorigenic secretome

Abstract

The hotspot mutation H1047R in the oncogenic PIK3CA gene is frequently detected in breast cancer and enhances the enzymatic activity of PI3K to activate AKT/mTOR signaling cascade. Aberrant elevated PI3K activation has been reported to promote the tumorigenesis of breast cancer, but the mechanisms underlying are still needed to be elucidated. Here, we found that continuously activating PIK3CAH1047R conferred human mammary epithelial MCF‐10A cells to cellular senescence upon serum‐starvation. Similarly, breast cancer T47D and HCC1954 cells harboring H1047R mutation were senescent when cells were deprived of serum. PI3K/AKT/mTOR axis but not p53 or RB might be required for the induction of senescence. Notably, membrane metallo‐endopeptidase (MME) was identified as a downstream effector of PI3K to mediate the induction of senescence, which might be associated with its glycosylation. Senescent cells elicited a distinct secretome dependent on PI3K and MME. Specifically, IL‐6 promoted the proliferation of normal cells and CCL2 induced the M2‐like polarization of macrophages, which might create an immunosuppressive microenvironment during the initiation and/or development of breast cancer. This study shed new light on the tumorigenesis induced by hyper‐activated PI3K and might provide new clues for the prevention and therapy of breast cancer.

Exploring the molecular mechanism of hepatitis virus inducing hepatocellular carcinoma by microarray data and immune infiltrates analysis

“…Since a large number of M2-type macrophages infiltrate HCC caused by HBV and HCV, and the activation of PI3K-Akt-mTOR pathway is related to the M2 polarization of macrophages (11,24), Through literature review, it was found that 13 differential genes (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), including mTOR, PIK3CA, AKT2, and PIK3CB, involved in the M2-type polarization of macrophages, according to the genes related to M2-type polarization. We first analyzed the expression of these 13 genes in HBV-HCC and HCV-HCC, and found that mTOR was down-regulated while other genes were up-regulated (Figure S3), which was consistent with the molecular characteristics of macrophage polarization.…”

Breast Cancer Prognosis Prediction and Immune Pathway Molecular Analysis Based on Mitochondria-Related Genes

“…This function could be reversed by the mutation status of the TP53 gene (which causes the p53 protein to gain GOF activity) [ 58 ]. The hotspot mutation H1047R in PI3KCA, frequently detected in BRCA, activates the PI3K/AKT/mTOR pathway and promotes BRCA tumor formation [ 59 ]. The described relationships between mutations and activated pathways are consistent with our results.…”

The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products

“…PI3K/AKT/mTOR is essential to induce senescence. Membrane metallo-endopeptidase (MME) is the downstream effector of PI3K to induce senescence [ 206 ]. Cervical cancers show low alpha2A-adrenergic receptor (ADRA2A) levels and poor prognoses [ 207 ].…”