PEA‑15 contributes to the clinicopathology and AKT‑regulated cisplatin resistance in gastric cancer

Abstract

Phosphoprotein enriched in astrocytes 15 (PEA-15) plays an important role in controlling biological behaviors of cancer cells. In the present study, we demonstrated that PEA-15 was overexpressed in gastric cancer tissues and associated with tumor staging, differentiation, pathological types and the prognosis of patients. Gastric cancer cells expressed variable levels of PEA-15 and its bi-phosphorylation forms, p-PEA-15 (Ser104) and p-PEA-15 (Ser116). To gain insight into the functional role of PEA-15, we generated cells stably depleted of PEA-15 and resistant to cisplatin (CDDP) from human gastric cancer cells. PEA-15 depletion inhibited cell proliferation by reducing cyclin D1 expression through the extracellular signal-regulated kinase (ERK) pathway, resulting in cell cycle arrest at the G1 phase, and induced apoptosis by activating caspase-8. PEA-15 depletion also enhanced the inhibitory effect of CDDP that caused cell cycle arrest at the S phase and also enhanced the pro-apoptotic activity of CDDP in vitro and in animal models of tumorigenesis and therapeutic effects. PEA-15 and its phosphorylated forms were overexpressed in CDDP-resistant cells, which had higher levels of p-AKT. Specific inhibition of AKT by MK2206 reduced the expression of p-PEA-15 at the Ser116 residue, resulting in sequential downregulation of p-ERK1/2, cyclin D1 and caspase-8 activation. However, depletion of PEA-15 had little effect on AKT expression or phosphorylation, or its downstream factors including p27, glycogen synthase kinase 3β and caspase-9, indicating that the regulatory effects between PEA-15 and AKT were unidirectional. In summary, the results indicated that PEA-15 expression was associated with clinicopathology and prognosis in gastric cancer and was regulated by AKT to participate in CDDP resistance, indicating that it may be a potential target for overcoming CDDP resistance in the treatment of gastric cancer.