| Eukaryotic translation initiation factor4E (eIF4E) plays a crucial role in several human tumors, including breast, head and neck, bladder, cervical, lung and prostate cancer, etc. Enhanced eIF4E function resulting from eIF4E overexpression or activation of the Ras and phosphatidylinositol3-kinase/Akt pathways can selectively upregulate the translation initiation of cancer-related mRNA, such as c-Myc, cyclin D1and Bcl-2for tumor growth, angiogenesis and cell survival. The overexpression or knockdown of eIF4E provides insights into its functional significance in tumorigenesis. Knockdown of eIF4E can suppress proliferation and angiogenesis. Additionally, elevated eIF4E expression confers resistance to multiple chemotherapy agents. A combination of chemotherapy with eIF4E silencing was reported to increase sensitivity to chemotherapeutic drugs such as cryptotanshinone, cisplatin, adriamycin, paclitaxel and docetaxel.Gastric cancer, a leading cause of cancer-related mortality worldwide, is the fourth most frequent malignancy. Despite marked improvements in surgical, chemo-, radio-and other adjuvant therapies, the5-year survival rate of patients at the advanced stage remains<20-25%, In recent years, emerging evidence has revealed various genetic changes involved in the progression of gastric cancer. It is critical to investigate the precise molecular mechanism of gastric cancer development for improved anticancer therapeutics.Perifosine is a synthetic alkylphosphocholine, exhibiting antitumor activity through blocking cell membrane recruitment of the N-terminal Akt pleckstrin homology (PH) domain. It also exerts an antitumor effect through MAPK pathway inhibition while inducing c-Jun NH2-terminal kinase (JNK) and upregulating death receptor5(DR5). The clinical efficacy of perifosine was evaluated in a phase I clinical trial in patients with advanced tumor. Perifosine showed potent anticancer efficacy in a various types of cancer, including breast, prostate and renal cell cancer. However, there has been no report on the effect of perifosine against human gastric cancer cells, and its molecular mechanism has yet to be fully elucidated.In the present study, we first examined the expression of total eIF4E (T-eIF4E) and phosphorylated eIF4E (p-eIF4E) in human tissues and gastric cancer cell lines. The results showed that the expression of T-eIF4E and p-eIF4E was increased in gastric cancer tissues and cell lines. We also analyzed the correlation between T-eIF4E and p-eIF4E levels and the clinicopathological characteristics of gastric cancer. A significant correlation was found between T-eIF4E overexpression and distance metastasis in patients (P=0.026). We then discussed the proliferation of human gastric cancer SGC7901and MGC803cells following eIF4E gene silencing. Downregulation of eIF4E significantly suppressed the proliferation of gastric cancer cells. Furthermore, we first observed perifosine inhibited the Akt/eIF4E signaling and has a significant cytotoxic effect on gastric cancer cells (SGC7901, MGC803, AGS and MKN45) in a dose-dependent manner. We further identified a combined effect of eIF4E small interfering RNA (siRNA) and perifosine on the growth of gastric cancer cells. The combination of eIF4E gene silencing and perifosine was more effective than eIF4E gene silencing or perifosine alone. After SGC7901and MGC803cells transfected with eIF4E siRNA or a control siRNA were treated with perifosine, eIF4E expression was further downregulated.Taken together, our results demonstrate that the oncogenic function of eIF4E and presented the possibility of eIF4E as an effective antitumor target in gastric cancer.. eIF4E inhibitors alone or in combination with perifosine may be a novel therapeutic approach against gastric cancer. |
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