Inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their synergistic growth inhibition of cancer cells

Kasukabe,Takashi; Okabe-Kado,Junko; Haranosono,Yu; Kato,Nobuo; Honma,Yoshio

doi:10.3892/ijo.2012.1745

Inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their synergistic growth inhibition of cancer cells

Authors:
- Takashi Kasukabe
- Junko Okabe-Kado
- Yu Haranosono
- Nobuo Kato
- Yoshio Honma
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Affiliations: Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama 362-0806, Japan, Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan, School of Medicine, Shimane University, Izumo 693-8501, Japan
Published online on: December 19, 2012 https://doi.org/10.3892/ijo.2012.1745
Pages: 767-775

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Abstract

Cotylenin A, a plant growth regulator, and rapamycin, an inhibitor of the mammalian target of rapamycin, are potent inducers of differentiation in myeloid leukemia cells and also synergistically inhibit the proliferation of several human breast cancer cell lines including MCF-7 in vitro and in vivo. However, the mechanisms of the combined effects of cotylenin A and rapamycin are still unknown. Activated Akt induced by rapamycin has been suggested to attenuate the growth-inhibitory effects of rapamycin, serving as a negative feedback mechanism. In this study, we found that cotylenin A could suppress rapamycin-induced phosphorylation of Akt (Ser473) in MCF-7 cells and lung carcinoma A549 cells and that cotylenin A also enhanced the rapamycin-induced growth inhibition of MCF-7 and A549 cells. ISIR-005 (a synthetic cotylenin A-derivative) was able to enhance rapamycin‑induced growth inhibition and could also markedly inhibit rapamycin-induced phosphorylation of Akt. We also found that the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) or arsenic trioxide (ATO) in combination with rapamycin markedly inhibited the growth of MCF-7 cells and 17-AAG or ATO suppressed rapamycin-induced phosphorylation of Akt. The PI3K inhibitor LY294002 also suppressed rapamycin-induced phosphorylation of Akt and combined treatment showed synergistic growth inhibition of MCF-7 cells. Rapamycin inhibited growth more significantly in Akt siRNA-transfected MCF-7 cells than in control siRNA-transfected MCF-7 cells. These results suggest that the inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their effective growth inhibition of cancer cells.

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