PMID- 24185040
OWN - NLM
STAT- MEDLINE
DCOM- 20140911
LR  - 20211203
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 4
IP  - 11
DP  - 2013 Nov
TI  - Selective targeting of human colon cancer stem-like cells by the mTOR inhibitor 
      Torin-1.
PG  - 1948-62
AB  - Metastatic colorectal cancer (CRC) is incurable for most patients. Since 
      mammalian target of rapamycin (mTOR) has been suggested as a crucial modulator of 
      tumor biology, we aimed at evaluating the effectiveness of mTOR targeting for CRC 
      therapy. To this purpose, we analyzed mTOR expression and the effect of mTOR 
      inhibition in cancer stem-like cells isolated from three human metastatic CRCs 
      (CoCSCs). CoCSCs exhibited a strong mTOR complex 2 (mTORC2) expression, and a 
      rare expression of mTOR complex 1 (mTORC1). This latter correlated with 
      differentiation, being expressed in CoCSC-derived xenografts. We indicate 
      Serum/glucocorticoid-regulated kinase 1 (SGK1) as the possible main mTORC2 
      effector in CoCSCs, as highlighted by the negative effect on cancer properties 
      following its knockdown. mTOR inhibitors affected CoCSCs differently, resulting 
      in proliferation, autophagy as well as apoptosis induction. The 
      apoptosis-inducing mTOR inhibitor Torin-1 hindered growth, motility, invasion, 
      and survival of CoCSCs in vitro, and suppressed tumor growth in vivo with a 
      concomitant reduction in vessel formation. Torin-1 also affected the expression 
      of markers for cell proliferation, angio-/lympho-genesis, and stemness in vivo, 
      including Ki67, DLL1, DLL4, Notch, Lgr5, and CD44. Importantly, Torin-1 did not 
      affect the survival of normal colon stem cells in vivo, suggesting its 
      selectivity towards cancer cells. Thus, we propose Torin-1 as a powerful drug 
      candidate for metastatic CRC therapy.
FAU - Francipane, Maria Giovanna
AU  - Francipane MG
AD  - McGowan Institute for Regenerative Medicine, Department of Pathology, University 
      of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
FAU - Lagasse, Eric
AU  - Lagasse E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 
      (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one)
RN  - 0 (Naphthyridines)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Growth Processes/drug effects
MH  - Cell Line, Tumor
MH  - Colonic Neoplasms/blood supply/*drug therapy/metabolism/pathology
MH  - Humans
MH  - Immunohistochemistry
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Naphthyridines/*pharmacology
MH  - Neoplastic Stem Cells/*drug effects/*metabolism/pathology
MH  - Neovascularization, Pathologic/drug therapy/metabolism/pathology
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC3875761
EDAT- 2013/11/05 06:00
MHDA- 2014/09/12 06:00
PMCR- 2013/11/01
CRDT- 2013/11/05 06:00
PHST- 2013/11/05 06:00 [entrez]
PHST- 2013/11/05 06:00 [pubmed]
PHST- 2014/09/12 06:00 [medline]
PHST- 2013/11/01 00:00 [pmc-release]
AID - 1310 [pii]
AID - 10.18632/oncotarget.1310 [doi]
PST - ppublish
SO  - Oncotarget. 2013 Nov;4(11):1948-62. doi: 10.18632/oncotarget.1310.