Phospholipase D confers rapamycin resistance in human breast cancer cells

Oncogene. 2003 Jun 19;22(25):3937-42. doi: 10.1038/sj.onc.1206565.

Abstract

mTOR (mammalian target of rapamycin) is a protein kinase that regulates cell cycle progression and cell growth. Rapamycin is a highly specific inhibitor of mTOR in clinical trials for the treatment of breast and other cancers. mTOR signaling was reported to require phosphatidic acid (PA), the metabolic product of phospholipase D (PLD). PLD, like mTOR, has been implicated in survival signaling and the regulation of cell cycle progression. PLD activity is frequently elevated in breast cancer. We have investigated the effect of rapamycin on breast cancer cell lines with different levels of PLD activity. MCF-7 cells, with relatively low levels of PLD activity, were highly sensitive to the growth-arresting effects of rapamycin, whereas MDA-MB-231 cells, with a 10-fold higher PLD activity than MCF-7 cells, were highly resistant to rapamycin. Elevating PLD activity in MCF-7 cells led to rapamycin resistance; and inhibition of PLD activity in MDA-MB-231 cells increased rapamycin sensitivity. Elevated PLD activity in MCF-7 cells also caused rapamycin resistance for S6 kinase phosphorylation and serum-induced Myc expression. These data implicate mTOR as a critical target for survival signals generated by PLD and suggest that PLD levels in breast cancer could be a valuable indicator of the likely efficacy of rapamycin treatment.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / pathology*
  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Cell Division / drug effects
  • Culture Media, Serum-Free / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Phospholipase D / genetics
  • Phospholipase D / physiology*
  • Phosphorylation / drug effects
  • Protein Kinases / physiology*
  • Protein Processing, Post-Translational / drug effects
  • Recombinant Fusion Proteins / physiology
  • Ribosomal Protein S6 Kinases / antagonists & inhibitors
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases

Substances

  • Culture Media, Serum-Free
  • Neoplasm Proteins
  • Recombinant Fusion Proteins
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases
  • phospholipase D2
  • Phospholipase D
  • phospholipase D1
  • Sirolimus