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  • Title: Inhibition of induced autophagy increases apoptosis of Nara-H cells.
    Author: Nakamura O, Hitora T, Akisue T, Kawamoto T, Yamagami Y, Yamamoto T.
    Journal: Int J Oncol; 2011 Dec; 39(6):1545-52. PubMed ID: 21805033.
    Abstract:
    Inhibition of the mTOR signaling pathway promotes initiation of autophagy. However, recent studies indicate that autophagy is a self-defense mechanism of cancer cells that are subjected to anti-tumor agents and that blocking autophagy can trigger apoptosis. Here, we examined the effects of an mTOR inhibitor, temsirolimus, on a malignant fibrous histiocytoma (MFH) cell line, Nara-H cells, and the effect of suppressing autophagy on the induction of apoptosis in these MFH cells. In Nara-H cells, we examined the effects of temsirolimus treatment on cell proliferation using the CellTiter 96® AQueous One Solution Cell Proliferation Assay and on phosphorylation of mTOR pathway components and autophagy using Western blot-based assays. Furthermore, we examined the effects of temsirolimus with or without 3-methyladenine (3-MA) on induction of apoptosis using fluorescent microscopic analysis. In Nara-H cells, temsirolimus treatment inhibited cell proliferation, suppressed phosphorylation of mTOR pathway components, and induced autophagy as assessed by LC-3 II expression. Moreover, treatment with a combination of temsirolimus and 3-MA induced apoptosis in Nara-H cells. Apparently, simultaneous inhibition of autophagy and mTOR induced apoptosis in Nara-H cells because inhibition of autophagy prevented the cells from protecting themselves from the effects of the inhibition of mTOR. Therefore, a combination therapy that includes an mTOR inhibitor and an autophagy inhibitor (temsirolimus and 3-MA, respectively) may effectively treat MFH by inducing apoptosis in tumor cells.
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