Prostaglandin E2 (PGE2) may influence skin aging and cancer risk, according to a new study in Aging.
PGE2 not only drives skin cells to age but also enables some of these aging cells to bypass natural limits and develop into pre-cancerous cells, providing insights into why older skin is more susceptible to cancer.
As keratinocytes age, they enter a state called senescence. While this process typically serves as a protective mechanism, in certain cases, some senescent cells can escape this state, re-enter the cell cycle, and acquire characteristics of early cancer. By examining keratinocytes from donors of different ethnicities and ages, the researchers identified the PTGS2/PGE2/EP4 pathway as a key driver of this escape process.
Blocking PGE2 or its associated pathway reduced the chances of aged cells becoming precancerous, the researchers note. This suggests that drugs targeting this pathway, including some anti-inflammatory medications already in use, might be repurposed to slow skin aging and prevent early-stage skin cancers.
Additionally, the study found that PGE2 levels increase in the skin as it ages, further supporting its role in skin health and disease.
IMAGE CAPTION:
FIGURE 2. PTGS2 INDUCES AND MAINTAINS NHEK SENESCENCE. (A) NHEKS (DONOR 4F0315) WERE TREATED WITH NS398 AT 5 OR 10 ΜM OR DMSO EVERY 48 H. LEFT PANEL: DURING THE TREATMENT, CELLS WERE PASSAGED WHEN REACHING 70% CONFLUENCE, COUNTED, AND THE NUMBER OF POPULATION DOUBLINGS WAS CALCULATED (SEE METHODS). THE EXPERIMENT WAS PERFORMED IN TRIPLICATE, EACH POINT REPRESENTING THE MEAN OF THREE COUNTS. SIGNIFICANT DIFFERENCES BETWEEN DMSO CONTROL AND 5 OR 10 ΜM NS398 TREATMENT ARE INDICATED. RIGHT PANEL: SENESCENT NHEKS WERE TREATED AS IN (A), THEN, A SA-Β-GAL ASSAY WAS PERFORMED SEVEN DAYS POST-TREATMENTS. (B) SENESCENT NHEKS (DONOR K23FC1) WERE TRANSFECTED WITH A POOL OF 4 SIRNAS TARGETING PTGS2, OR WITH NON-TARGET SIRNAS. LEFT PANEL: EVALUATION OF THE EFFICACY OF THE SIRNAS BY WESTERN BLOT. GAPDH WAS USED AS A LOADING CONTROL. RIGHT PANEL: FOUR DAYS AFTER TRANSFECTION, A SA-Β-GAL ASSAY WAS PERFORMED. THE BARS REPRESENT THE MEAN ±SD OF THREE COUNTS OF BLUE CELLS (**P < 0.01). (C) SENESCENT NHEKS (DONOR K23FC1) WERE TREATED WITH NS398 OR ROFECOXIB AT THE INDICATED CONCENTRATIONS FOR FOUR DAYS. THEN, A SA-Β-GAL ASSAY WAS PERFORMED. THE BARS REPRESENT THE MEAN ±SD OF THREE COUNTS OF BLUE CELLS (*P < 0.05; **P < 0.01). (D) ELISA ASSAYS FOR MEASURING THE AMOUNTS OF GM-CSF AND G-CSF IN THE CONDITIONED MEDIA (SECRETED) OF EXPONENTIALLY GROWING, PRE-SENESCENT AND SENESCENT NHEKS (DONOR K40FH1) TREATED OR NOT WITH NS398 (5 ΜM) FOR 16 HRS. MEASURES WERE PERFORMED IN TRIPLICATE. THE BARS REPRESENT THE MEAN ± SD OF THREE COUNTS. SIGNIFICANT DIFFERENCES ARE INDICATED WITH ASTERISKS WITH *P < 0.05; **P < 0.01; ***P < 0.001.
