Defective TGF-beta signaling sensitizes human cancer cells to rapamycin

Oncogene. 2008 Feb 14;27(8):1055-62. doi: 10.1038/sj.onc.1210721. Epub 2007 Aug 13.

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Sirolimus / pharmacology*
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / physiology*

Substances

  • Antibiotics, Antineoplastic
  • Transforming Growth Factor beta
  • Sirolimus