Defective TGF-β signaling sensitizes human cancer cells to rapamycin

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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.