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Defective TGF-β signaling sensitizes human cancer cells to rapamycin

Oncogene volume 27, pages 1055–1062 (2008)Cite this article

Abstract

mTOR, the mammalian target of rapamycin, is a critical target of survival signals in many human cancers. In the absence of serum, rapamycin induces apoptosis in MDA-MB-231 human breast cancer cells. However, in the presence of serum, rapamycin induces G1 cell cycle arrest—indicating that a factor(s) in serum suppresses rapamycin-induced apoptosis. We report here that transforming growth factor-β (TGF-β) suppresses rapamycin-induced apoptosis in serum-deprived MDA-MB-231 cells in a protein kinase Cδ (PKCδ)-dependent manner. Importantly, if TGF-β signaling or PKCδ was suppressed, rapamycin induced apoptosis rather than G1 arrest in the presence of serum. And, if cells were allowed to progress into S phase, rapamycin induced apoptosis in the presence of serum. BT-549 and MDA-MB-468 breast, and SW-480 colon cancer cells have defects in TGF-β signaling and rapamycin induced apoptosis in these cells in the presence of either serum or TGF-β. Thus, in the absence of TGF-β signaling, rapamycin becomes cytotoxic rather than cytostatic. Importantly, this study provides evidence indicating that tumors with defective TGF-β signaling—common in colon and pancreatic cancers—will be selectively sensitive to rapamycin or other strategies that target mTOR.

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Acknowledgements

This work was supported by grants from the National Cancer Institute CA46677 and a SCORE grant from the National Institutes of Health GM60654. Research Centers in Minority Institutions award RR-03037 from the National Center for Research Resources of the National Institutes of Health, which supports infrastructure and instrumentation in the Biological Sciences Department at Hunter College, is also acknowledged.

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  1. Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA

    N Gadir, D N Jackson, E Lee & D A Foster

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  1. N Gadir
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Correspondence to D A Foster.

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Gadir, N., Jackson, D., Lee, E. et al. Defective TGF-β signaling sensitizes human cancer cells to rapamycin. Oncogene 27, 1055–1062 (2008). https://doi.org/10.1038/sj.onc.1210721

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