Rapamycin induces Smad activity in prostate cancer cell lines

H. G. Van der Poel, C. Hanrahan, H. Zhong, J. W. Simons

Research output: Contribution to journalArticle

Abstract

Rapamycin inhibits the FK506-binding protein 12 (FKBP12)/mammalian target of rapamycin (mTOR) complex and causes cell cycle arrest in G1. The precise mechanism of growth inhibition by rapamycin is only partly understood. Rapamycin led to growth inhibition in the human prostate cancer cell lines LNCaP and PC3 cells after 72 h, ID50: 93 and 50 nM, respectively. Filter cDNA array analysis showed down-regulation by more than 0.75x by rapamycin in PC3 cells and LNCaP cells of the following genes: follistatin, eukaryotic initiation factor-4E (eIF4E), glucose-6-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH)-A, ATP synthase, heat shock protein (HSP)-1. Upregulation by more than 1.5 x was found for: bone morphogenetic protein (BMP)-4, FKBP12, carcinoma embryonic antigen (CEA) precursor, eukaryotic initiation factor (eIF)-3 p36 subunit, latent transforming growth factor (TGF) beta binding protein (LTBP)1. Rapamycin induced BMP4 and reduced follistatin expression in PC3 cells. This resulted in a dose-dependent nuclear expression of Smad4 and activated the SBE4 Smad-reporter, indicating activation of TGFbeta/BMP signaling. Combining rapamycin with PI3K inhibition (LY294002) increased growth inhibition. These findings illustrate that Smad signaling plays a role in the anticancer effects of rapamycin and show that combination with PI3K inhibition improves growth inhibition.

Original languageEnglish (US)
Pages (from-to)380-386
Number of pages7
JournalUrological Research
Volume30
Issue number6
StatePublished - Feb 1 2003

Keywords

  • Bone morphogenetic protein
  • Follistatin
  • Mammalian target of rapamycin (mTOR)
  • Prostate cancer
  • Rapamycin
  • Transforming growth factor (TGF)

ASJC Scopus subject areas

  • Urology

Fingerprint Dive into the research topics of 'Rapamycin induces Smad activity in prostate cancer cell lines'. Together they form a unique fingerprint.

  • Cite this

    Van der Poel, H. G., Hanrahan, C., Zhong, H., & Simons, J. W. (2003). Rapamycin induces Smad activity in prostate cancer cell lines. Urological Research, 30(6), 380-386.