Upregulation of the eIF4E signaling pathway contributes to the progression of gastric cancer, and targeting eIF4E by perifosine inhibits cell growth

Liang,Song; Guo,Renhua; Zhang,Zhihong; Liu,Dongxiao; Xu,Hao; Xu,Zekuan; Wang,Xuerong; Yang,Li

doi:10.3892/or.2013.2397

Upregulation of the eIF4E signaling pathway contributes to the progression of gastric cancer, and targeting eIF4E by perifosine inhibits cell growth

Authors:
- Song Liang
- Renhua Guo
- Zhihong Zhang
- Dongxiao Liu
- Hao Xu
- Zekuan Xu
- Xuerong Wang
- Li Yang
View Affiliations

Affiliations: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China, Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China, Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China, Department of General Surgery, The Second Affiliated Hospital of South-east University, The Second Hospital of Nanjing, Nanjing, P.R. China, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
Published online on: April 9, 2013 https://doi.org/10.3892/or.2013.2397
Pages: 2422-2430

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The increase of eukaryotic translation initiation factor 4E (eIF4E) expression is frequently observed in several types of cancer, making eIF4E an attractive anticancer drug target. However, the role of eIF4E in gastric cancer pathogenesis remains unclear. Perifosine is a bioavailable alkylphospholipid exhibiting antitumor activity in a series of cancer types. In this study, gastric cancer cell lines were selected to explore the role of eIF4E as a potential target for treating human gastric cancer. The expression of total eIF4E (T-eIF4E)and phosphorylated eIF4E (p-eIF4E) in gastric cancer samples was detected by immunohistochemical assay. RNA interference was used to silence eIF4E expression. Sulforhodamine B assay was performed to evaluate tumor cell viability. Colony formation assay was used to examine the effects of eIF4E small interfering RNA (siRNA) or perifosine on colony formation. The mRNA levels of eIF4E were analyzed by qRT-PCR and western blot analysis was carried out to evaluate the expression of Akt and eIF4E. The results showed that increased expression levels of T-eIF4E and p-eIF4E were found in gastric cancer tissues and cells. Reduced eIF4E expression blocked the proliferation of gastric cancer cells. Perifosine downregulated the T-eIF4E and p-eIF4E levels in a dose- and time-dependent manner; it also inhibited the growth of gastric cancer cells. Moreover, this inhibitory effect was significantly enhanced by the combination of eIF4E siRNA and perifosine treatments. Our results indicate that eIF4E gene silencing can inhibit tumor cell growth, and eIF4E can be developed as a promising therapeutic target for gastric cancer.

View Figures

View References

1	Avdulov S, Li S, Michalek V, et al: Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell. 5:553–563. 2004. View Article : Google Scholar : PubMed/NCBI
2	Chen CN, Hsieh FJ, Cheng YM, Lee PH and Chang KJ: Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J Surg Oncol. 86:22–27. 2004. View Article : Google Scholar : PubMed/NCBI
3	De Benedetti A and Graff JR: eIF-4E expression and its role in malignancies and metastases. Oncogene. 23:3189–3199. 2004.PubMed/NCBI
4	Dong K, Wang R, Wang X, et al: Tumor-specific RNAi targeting eIF4E suppresses tumor growth, induces apoptosis and enhances cisplatin cytotoxicity in human breast carcinoma cells. Breast Cancer Res Treat. 113:443–456. 2009.PubMed/NCBI
5	Choi CH, Lee JS, Kim SR, et al: Direct inhibition of eIF4E reduced cell growth in endometrial adenocarcinoma. J Cancer Res Clin Oncol. 137:463–469. 2011. View Article : Google Scholar : PubMed/NCBI
6	Herbert TP, Fahraeus R, Prescott A, Lane DP and Proud CG: Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E. Curr Biol. 10:793–796. 2000. View Article : Google Scholar : PubMed/NCBI
7	Ge Y, Cheng R, Zhou Y, et al: Cryptotanshinone induces cell cycle arrest and apoptosis of multidrug resistant human chronic myeloid leukemia cells by inhibiting the activity of eukaryotic initiation factor 4E. Mol Cell Biochem. 368:17–25. 2012. View Article : Google Scholar
8	Zhou FF, Yan M, Guo GF, et al: Knockdown of eIF4E suppresses cell growth and migration, enhances chemosensitivity and correlates with increase in Bax/Bcl-2 ratio in triple-negative breast cancer cells. Med Oncol. 28:1302–1307. 2011. View Article : Google Scholar : PubMed/NCBI
9	Gills JJ and Dennis PA: Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep. 11:102–110. 2009. View Article : Google Scholar : PubMed/NCBI
10	Elrod HA, Lin YD, Yue P, et al: The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway. Mol Cancer Ther. 6:2029–2038. 2007. View Article : Google Scholar
11	Papa V, Tazzari PL, Chiarini F, et al: Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia. 22:147–160. 2008. View Article : Google Scholar : PubMed/NCBI
12	Tazzari PL, Tabellini G, Ricci F, et al: Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor perifosine in acute myelogenous leukemia cells. Cancer Res. 68:9394–9403. 2008. View Article : Google Scholar : PubMed/NCBI
13	Leighl NB, Dent S, Clemons M, et al: A Phase 2 study of perifosine in advanced or metastatic breast cancer. Breast Cancer Res Treat. 108:87–92. 2008. View Article : Google Scholar : PubMed/NCBI
14	Ghobrial IM, Roccaro A, Hong F, et al: Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia. Clin Cancer Res. 16:1033–1041. 2010. View Article : Google Scholar
15	Cho DC, Hutson TE, Samlowski W, et al: Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy. Cancer. 118:6055–6062. 2012. View Article : Google Scholar
16	Ma Z, Zhu L, Luo X, Zhai S, Li P and Wang X: Perifosine enhances mTORC1-targeted cancer therapy by activation of GSK3β in NSCLC cells. Cancer Biol Ther. 13:1009–1017. 2012.PubMed/NCBI
17	Wang S, Rosenwald IB, Hutzler MJ, et al: Expression of the eukaryotic translation initiation factors 4E and 2alpha in non-Hodgkin's lymphomas. Am J Pathol. 155:247–255. 1999. View Article : Google Scholar
18	Muta D, Makino K, Nakamura H, Yano S, Kudo M and Kuratsu J: Inhibition of eIF4E phosphorylation reduces cell growth and proliferation in primary central nervous system lymphoma cells. J Neurooncol. 101:33–39. 2011.
19	Soni A, Akcakanat A, Singh G, et al: eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling. Mol Cancer Ther. 7:1782–1788. 2008. View Article : Google Scholar
20	Fan SQ, Ramalingam SS, Kauh J, Xu ZH, Khuri FR and Sun SY: Phosphorylated eukaryotic translation initiation factor 4 (eIF4E) is elevated in human cancer tissues. Cancer Biol Ther. 8:1463–1469. 2009. View Article : Google Scholar : PubMed/NCBI
21	Wheater MJ, Johnson PW and Blaydes JP: The role of MNK proteins and eIF4E phosphorylation in breast cancer cell proliferation and survival. Cancer Biol Ther. 10:728–735. 2010. View Article : Google Scholar : PubMed/NCBI
22	Fischer PM: Cap in hand: targeting eIF4E. Cell Cycle. 8:2535–2541. 2009. View Article : Google Scholar : PubMed/NCBI
23	Jia Y, Polunovsky V, Bitterman PB and Wagner CR: Cap-dependent translation initiation factor eIF4E: an emerging anticancer drug target. Med Res Rev. 32:786–814. 2012. View Article : Google Scholar : PubMed/NCBI
24	Hideshima T, Catley L, Yasui H, et al: Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 107:4053–4062. 2006. View Article : Google Scholar : PubMed/NCBI
25	Yoshizawa A, Fukuoka J, Shimizu S, et al: Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. Clin Cancer Res. 16:240–248. 2010. View Article : Google Scholar