title: mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells.
abstract: 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.
authors.affiliation: Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Tokuzo
authors.initials: T
authors.lastname: Arao
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tanaka
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kaneda
authors.forename: Kanae
authors.initials: K
authors.lastname: Kudo
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Fujita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tamura
authors.forename: Keiichi
authors.initials: K
authors.lastname: Aomatsu
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000494:pharmacology; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D002867:Chromones; D006023:Glycoproteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009025:Morpholines; C000606023:PROM1 protein, human; D010455:Peptides; D012333:RNA, Messenger; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D016559:Tacrolimus