Akt1 inhibition promotes breast cancer metastasis through EGFR-mediated ß-catenin nuclear accumulation.

BACKGROUND: Knockdown of Akt1 promotes Epithelial-to-Mesenchymal Transition in breast cancer cells. However, the mechanisms are not completely understood. METHODS: Western blotting, immunofluorescence, luciferase assay, real time PCR, ELISA and Matrigel invasion assay were used to investigate how Akt1 inhibition promotes breast cancer cell invasion in vitro. Mouse model of lung metastasis was used to measure in vivo efficacy of Akt inhibitor MK2206 and its combination with Gefitinib. RESULTS: Knockdown of Akt1 stimulated ß-catenin nuclear accumulation, resulting in breast cancer cell invasion. ß-catenin nuclear accumulation induced by Akt1 inhibition depended on the prolonged activation of EGFR signaling pathway in breast cancer cells. Mechanistic experiments documented that knockdown of Akt1 inactivates PIKfyve via dephosphorylating of PIKfyve at Ser318 site, resulting in a decreased degradation of EGFR signaling pathway. Inhibition of Akt1 using MK2206 could induce an increase in the expression of EGFR and ß-catenin in breast cancer cells. In addition, MK2206 at a low dosage enhance breast cancer metastasis in a mouse model of lung metastasis, while an inhibitor of EGFR tyrosine kinase Gefitinib could potentially suppress breast cancer metastasis induced by Akt1 inhibition. CONCLUSION: EGFR-mediated ß-catenin nuclear accumulation is critical for Akt1 inhibition-induced breast cancer metastasis.

Inhibition of PIKfyve using YM201636 suppresses the growth of liver cancer via the induction of autophagy.

Liver cancer is among the most common types of cancer worldwide. The aim of the present study was to investigate whether the phosphatidylinositol­3­phosphate 5­kinase (PIKfyve) inhibitor, YM201636, exerts anti­proliferative effects on liver cancer. The methods used in the present study included MTT assay, flow cytometry, western blot analysis and an allograft mouse model of liver cancer. The results revealed that YM201636 inhibited the proliferation of HepG2 and Huh­7 cells in a dose­dependent manner. HepG2 and Huh­7 cells exhibited strong monodansylcadaverine staining following treatment with YM201636. Accordingly, YM201636 treatment increased the expression of the autophagosome­associated marker protein microtubule­associated 1A/1B light chain 3­II in HepG2 and Huh­7 cells. The autophagy inhibitor 3­methyladenine attenuated the inhibitory effects of YM201636 on liver cancer cell proliferation. Further in vivo analysis revealed that YM201636 (2 mg/kg) inhibited tumor growth without notable systemic toxicity. Mechanistic experiments demonstrated that YM201636 induced­autophagy is dependent upon epidermal growth factor receptor (EGFR) overexpression in HepG2 and Huh­7 cells. Collectively, these results suggested that the PIKfyve inhibitor YM201636 may inhibit tumor growth by promoting EGFR expression. This indicates that PIKfyve may be a potential therapeutic target for the treatment of liver cancer.

MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing ß-catenin nuclear accumulation.

Abnormal activation of the RAF/MEK/ERK signaling pathway has been observed in breast cancer. Thus, a number of MEK inhibitors have been designed as one treatment option for breast cancer. Although some studies have found that these MEK inhibitors inhibit the growth of a variety of human cancer cells, some trials have shown that the use of MEK inhibitors as a treatment for breast cancer does not adequately improve survival for unknown reasons. In the present study, MEK inhibitor PD98059 was used to evaluate its anticancer effects on human breast cancer MCF-7 and MDA-MB-231 cells and to explore the possible mechanism of action. Our results revealed that MEK inhibitor PD98059 exhibited antiproliferative effects in a dose- and time-dependent manner in MCF-7 and MDA-MB-231 breast cancer cells. Conversely, incubation of MCF-7 and MDA-MB-231 cells with PD98059 promoted their migration. Further investigation disclosed that the enhanced ability of migration promoted by PD98059 was dependent on ß-catenin nuclear translocation in the MCF-7 and MDA-MB­231 cells. Subsequent experiments documented that activation of EGFR signaling induced by PD98059 increased the amount of ß-catenin in the nucleus. Taken together, our findings may elucidate a possible mechanism explaining the ineffectiveness of MEK inhibitors in breast cancer treatment and improve our understanding of the role of MEK in cancer.