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.

• Authors: Xian Jiang, Changlu Zhang, Weidong Li, Dalei Jiang, Zheng Wei, Mei Lv, Xiangjun Xie, Xueying Sun
• Journal: Oncology reports (Oncol Rep) Vol. 41 Issue 3 Pg. 1949-1959 (Mar 2019) ISSN: 1791-2431 [Electronic] Greece
• PMID: 30569123 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Intracellular Signaling Peptides and Proteins
• PEA15 protein, human
• Phosphoproteins
• RNA, Small Interfering
• Proto-Oncogene Proteins c-akt
• Cisplatin

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis
• Apoptosis Regulatory Proteins
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Down-Regulation
• Drug Resistance, Neoplasm
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Kaplan-Meier Estimate
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Phosphoproteins (genetics, metabolism)
• Phosphorylation
• Prognosis
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (metabolism)
• Stomach Neoplasms (drug therapy, mortality, pathology)
• Xenograft Model Antitumor Assays