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Eupafolin suppresses prostate cancer by targeting phosphatidylinositol 3-kinase-mediated Akt signaling.

ABSTRACT: Phosphatase and tensin homolog (PTEN) loss or mutation consistently activates the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway, which contributes to the progression and invasiveness of prostate cancer. Furthermore, the PTEN/PI3-K/Akt and Ras/MAPK pathways cooperate to promote the epithelial-mesenchymal transition (EMT) and metastasis initiated from prostate stem/progenitor cells. For these reasons, the PTEN/PI3-K/Akt pathway is considered as an attractive target for both chemoprevention and chemotherapy. Herein we report that eupafolin, a natural compound found in common sage, inhibited proliferation of prostate cancer cells. Protein content analysis indicated that phosphorylation of Akt and its downstream kinases was inhibited by eupafolin treatment. Pull-down assay and in vitro kinase assay results indicated that eupafolin could bind with PI3-K and attenuate its kinase activity. Eupafolin also exhibited tumor suppressive effects in vivo in an athymic nude mouse model. Overall, these results suggested that eupafolin exerts antitumor effects by targeting PI3-K.

SUBMITTER: Liu K

PROVIDER: S-EPMC4242796 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Eupafolin suppresses prostate cancer by targeting phosphatidylinositol 3-kinase-mediated Akt signaling.

Liu Kangdong K Park Chanmi C Chen Hanyong H Hwang Joonsung J Thimmegowda N R NR Bae Eun Young EY Lee Ki Won KW Kim Hong-Gyum HG Liu Haidan H Soung Nak Kyun NK Peng Cong C Jang Jae Hyuk JH Kim Kyoon Eon KE Ahn Jong Seog JS Bode Ann M AM Dong Ziming Z Kim Bo Yeon BY Dong Zigang Z

Molecular carcinogenesis 20140404 9

Phosphatase and tensin homolog (PTEN) loss or mutation consistently activates the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway, which contributes to the progression and invasiveness of prostate cancer. Furthermore, the PTEN/PI3-K/Akt and Ras/MAPK pathways cooperate to promote the epithelial-mesenchymal transition (EMT) and metastasis initiated from prostate stem/progenitor cells. For these reasons, the PTEN/PI3-K/Akt pathway is considered as an attractive target for both chemoprev ...[more]

PMID: 24700667

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Project description:BackgroundEukaryotic initiation factor 3 (eIF3) is the largest translation initiation factor, and oncogenic roles have been discovered for its subunits, including the f subunit (ie, eIF3f), in various human cancers. However, the roles of eIF3f in the development and progression of prostate cancer (PCa) have not been reported.Materials and methodsWe performed in silico analysis to screen the expression of eIF3 subunits. Relevant shRNAs were used to knock down eIF3 subunits in 22Rv1 cells and cell proliferation was analyzed. eIF3f expression in PCa specimens was confirmed by immunohistochemistry. eIF3f knockdown was established to evaluate the effects of eIF3f on cell proliferation in vitro and in vivo. RNA-seq, bioinformatics analysis and Western blotting were applied to explore the molecular details underlying the biological function of eIF3f in PCa cells. shRNA-resistant eIF3f and myristoylated-Akt were used to rescue the effects of eIF3f disturbance on PCa cells.ResultsFunctional analyses confirmed that eIF3f is essential for PCa proliferation. Notably, the expression of eIF3f was found to be elevated in human PCa tissues as well as in PCa cell lines. eIF3f silencing significantly suppressed the growth of PCa cells, both in vitro and in vivo. eIF3f expression was positively correlated with Akt signaling activity in RNA-seq profiles and published prostate cohorts. Knockdown of eIF3f markedly reduced the levels of phosphorylated Akt in PCa cells. Exogenous expression of shRNA-resistant eIF3f in eIF3f knockdown cells restored Akt phosphorylation levels and cell growth. Importantly, rescue experiments revealed that ectopic expression of myristoylated-Akt partially alleviated the suppressive effects of eIF3f disturbance with respect to the growth of PCa cells.ConclusionThese results suggested that eIF3f has an oncogenic role in PCa, mediated at least partially through the regulation of Akt signaling, and that eIF3f represents a potential target for the inhibition of PCa growth and progression.

Dataset Information

Eupafolin suppresses prostate cancer by targeting phosphatidylinositol 3-kinase-mediated Akt signaling.

Publications

Eupafolin suppresses prostate cancer by targeting phosphatidylinositol 3-kinase-mediated Akt signaling.

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