2-Methoxyestradiol attenuates phosphatidylinositol 3-kinase/Akt pathway-mediated metastasis of gastric cancer

Heng Liang Lin, Muh Hwa Yang, Chew Wun Wu, Po Min Chen, Yi Ping Yang, Yue Ru Chu, Chung Lan Kao, Hung Hai Ku, Jen Fan Lo, Jing Ping Liou, Chin Wen Chi, Shih Hwa Chiou

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Abstract

The major obstacle for the treatment of gastric cancer is recurrence and metastasis; yet, its molecular mechanism is largely unknown. 2-methoxyestradiol (2-ME), a metabolite of the estradiol-17β, has recently been demonstrated to have multifactorial effects against tumor proliferation and angiogenesis; how these effects are interrelated and act cooperatively is the key question to be elucidated. Akt activation was shown to promote cancer cell invasiveness, and inhibition of Akt phosphorylation by 2-ME was also noted. We herein investigated the significance of PI3K/Akt activation in gastric cancer metastasis and the anti-metastatic effect of 2-ME through attenuation of Akt activity. Immunohistochemistry of PI3K, phosphorylated Akt (p-Akt) and phosphorylated Erk (p-Erk) was performed in tumors from 56 gastric cancer patients, and a significant correlation between PI3K/p-Akt and tumor stage/prognosis was demonstrated (p <0.05). An in vitro study of 7 gastric cancer cell lines showed a remarkable correlation between PI3K and p-Akt. PI3K/p-Akt overexpression was associated with invasiveness/migration; in contrast, phosphorylation of Erk was not shown to be correlated with invasiveness. In addition, metastatic gastric cancer clones expressed a higher level of PI3K/p-Akt. The anti-metastatic effect of a low dose of 2-ME and inactivation of Akt was demonstrated. 2-ME also exhibited an ability to inhibit gastric cancer cell proliferation and induce G2/M cell cycle arrest at a higher concentration than that required for inhibition of migration. We conclude that the activation of PI3K/Akt pathway is involved in the late-stage progression and metastasis of gastric cancer, and attenuation of p-Akt by 2-ME suppresses metastasis.

Original languageEnglish
Pages (from-to)2547-2555
Number of pages9
JournalInternational Journal of Cancer
Volume121
Issue number11
DOIs
Publication statusPublished - Dec 1 2007

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Keywords

  • 2-methoxyestradiol
  • Akt
  • Gastric cancer
  • Green fluorescent protein
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lin, H. L., Yang, M. H., Wu, C. W., Chen, P. M., Yang, Y. P., Chu, Y. R., Kao, C. L., Ku, H. H., Lo, J. F., Liou, J. P., Chi, C. W., & Chiou, S. H. (2007). 2-Methoxyestradiol attenuates phosphatidylinositol 3-kinase/Akt pathway-mediated metastasis of gastric cancer. International Journal of Cancer, 121(11), 2547-2555. https://doi.org/10.1002/ijc.22963