Defective TGF-beta signaling sensitizes human cancer cells to rapamycin.
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 G(1) 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 Cdelta (PKCdelta)-dependent manner. Importantly, if TGF-beta signaling or PKCdelta was suppressed, rapamycin induced apoptosis rather than G(1) 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.
Gadir
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N
Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10021, USA.
Jackson
D N
DN
Lee
E
E
Foster
D A
DA
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*
D000903:Antibiotics, Antineoplastic; D016212:Transforming Growth Factor beta; D020123:Sirolimus