PMID- 19738050
OWN - NLM
STAT- MEDLINE
DCOM- 20091007
LR  - 20211203
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 69
IP  - 18
DP  - 2009 Sep 15
TI  - mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in 
      cancer cells.
PG  - 7160-4
LID - 10.1158/0008-5472.CAN-09-1289 [doi]
AB  - The underlying mechanism regulating the expression of the cancer stem 
      cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains 
      largely unclear, although knowledge of this mechanism would likely provide 
      important biological information regarding cancer stem cells. Here, we found that 
      the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA 
      and protein levels in a CD133-overexpressing cancer cell line. This effect was 
      canceled by a rapamycin-competitor, tacrolimus, and was not modified by 
      conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1 
      alpha (HIF-1 alpha), a downstream molecule in the mTOR signaling pathway, might 
      regulate CD133 expression; we therefore investigated the relation between CD133 
      and HIF-1 alpha. Hypoxic conditions up-regulated HIF-1 alpha expression and 
      inversely down-regulated CD133 expression at both the mRNA and protein levels. 
      Similarly, the HIF-1 alpha activator deferoxamine mesylate dose-dependently 
      down-regulated CD133 expression, consistent with the effects of hypoxic 
      conditions. Finally, the correlations between CD133 and the expressions of HIF-1 
      alpha and HIF-1 beta were examined using clinical gastric cancer samples. A 
      strong inverse correlation (r = -0.68) was observed between CD133 and HIF-1 
      alpha, but not between CD133 and HIF-1 beta. In conclusion, these results 
      indicate that HIF-1 alpha down-regulates CD133 expression and suggest that mTOR 
      signaling is involved in the expression of CD133 in cancer cells. Our findings 
      provide a novel insight into the regulatory mechanisms of CD133 expression via 
      mTOR signaling and HIF-1 alpha in cancer cells and might lead to insights into 
      the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in 
      the maintenance of stemness in cancer stem cells.
FAU - Matsumoto, Kazuko
AU  - Matsumoto K
AD  - Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, 
      Osaka, Japan.
FAU - Arao, Tokuzo
AU  - Arao T
FAU - Tanaka, Kaoru
AU  - Tanaka K
FAU - Kaneda, Hiroyasu
AU  - Kaneda H
FAU - Kudo, Kanae
AU  - Kudo K
FAU - Fujita, Yoshihiko
AU  - Fujita Y
FAU - Tamura, Daisuke
AU  - Tamura D
FAU - Aomatsu, Keiichi
AU  - Aomatsu K
FAU - Tamura, Tomohide
AU  - Tamura T
FAU - Yamada, Yasuhide
AU  - Yamada Y
FAU - Saijo, Nagahiro
AU  - Saijo N
FAU - Nishio, Kazuto
AU  - Nishio K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090908
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (AC133 Antigen)
RN  - 0 (Antigens, CD)
RN  - 0 (Chromones)
RN  - 0 (Glycoproteins)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Morpholines)
RN  - 0 (PROM1 protein, human)
RN  - 0 (Peptides)
RN  - 0 (RNA, Messenger)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - AC133 Antigen
MH  - Antigens, CD/*biosynthesis/genetics
MH  - Cell Line, Tumor
MH  - Chromones/pharmacology
MH  - Colorectal Neoplasms/genetics/metabolism
MH  - Down-Regulation/drug effects
MH  - Glycoproteins/*biosynthesis/genetics
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/*metabolism
MH  - Lung Neoplasms/genetics/metabolism
MH  - Morpholines/pharmacology
MH  - Neoplasms/genetics/*metabolism
MH  - Peptides/genetics
MH  - Protein Kinases/*metabolism
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - Stomach Neoplasms/genetics/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Tacrolimus/pharmacology
MH  - Transcription, Genetic
MH  - Up-Regulation/genetics
EDAT- 2009/09/10 06:00
MHDA- 2009/10/08 06:00
CRDT- 2009/09/10 06:00
PHST- 2009/09/10 06:00 [entrez]
PHST- 2009/09/10 06:00 [pubmed]
PHST- 2009/10/08 06:00 [medline]
AID - 0008-5472.CAN-09-1289 [pii]
AID - 10.1158/0008-5472.CAN-09-1289 [doi]
PST - ppublish
SO  - Cancer Res. 2009 Sep 15;69(18):7160-4. doi: 10.1158/0008-5472.CAN-09-1289. Epub 
      2009 Sep 8.