title: Comparative effects of PP242 and rapamycin on mTOR signalling and NOTCH signalling in leukemia cells.
abstract: OBJECTIVE
  PP242 is a compound which inhibits both mammalian target of rapamycin complex-1 (mTORC1) and mTORC2. We examined the effects of PP242 and rapamycin on mTOR signalling and evaluated potential crosstalk with the NOTCH signalling in eight leukemia cell lines.
  
  
  METHODS
  We examined the effects of treatment with these inhibitors on cell growth and protein expression.
  
  
  RESULTS
  PP242 suppressed growth more potently than did rapamycin. In two cell lines poorly sensitive to PP242, PP242 failed to inhibit v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation. Suppression of mTOR phosphorylation was weaker in myeloid cell lines. Rapamycin induced eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation in three cell lines. Phosphorylation of both isoforms (p70 and p85) of S6 kinase (S6K) was suppressed in three cell lines; only p70 was suppressed in the others. NOTCH1 expression and activation were up-regulated by PP242 in one cell line but down-regulated in another.
  
  
  CONCLUSIONS
  PP242 is a candidate for molecular-targeted leukemia therapy, although its effects must be evaluated on a case-by-case basis. Crosstalk was found between the mTOR and NOTCH signalling pathways.
authors.affiliation: Department of Laboratory Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo 113-8519, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Ono
authors.forename: Ryo
authors.initials: R
authors.lastname: Oike
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okuhashi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Mai
authors.initials: M
authors.lastname: Itoh
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nara
authors.forename: Shuji
authors.initials: S
authors.lastname: Tohda
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology*; D051880:Receptors, Notch / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D007211:Indoles; D011687:Purines; D051880:Receptors, Notch; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus