期刊
ONCOGENE
卷 27, 期 8, 页码 1055-1062出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210721
关键词
rapamycin; mTOR; TGF-beta; PKC delta; cancer
资金
- NCI NIH HHS [CA46677] Funding Source: Medline
- NCRR NIH HHS [RR-03037] Funding Source: Medline
- NIGMS NIH HHS [GM60654] Funding Source: Medline
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-beta (TGF-beta) suppresses rapamycin-induced apoptosis in serum-deprived MDA-MB-231 cells in a protein kinase C delta (PKC delta)-dependent manner. Importantly, if TGF-beta signaling or PKCd 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-beta signaling and rapamycin induced apoptosis in these cells in the presence of either serum or TGF-beta. Thus, in the absence of TGF-beta signaling, rapamycin becomes cytotoxic rather than cytostatic. Importantly, this study provides evidence indicating that tumors with defective TGF-beta signaling - common in colon and pancreatic cancers - will be selectively sensitive to rapamycin or other strategies that target mTOR.
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