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: Kazuko Matsumoto, Tokuzo Arao, Kaoru Tanaka, Hiroyasu Kaneda, Kanae Kudo, Yoshihiko Fujita, Daisuke Tamura, Keiichi Aomatsu, Tomohide Tamura, Yasuhide Yamada, Nagahiro Saijo, Kazuto Nishio
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 18 Pg. 7160-4 (Sep 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19738050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AC133 Antigen
• Antigens, CD
• Chromones
• Glycoproteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Morpholines
• PROM1 protein, human
• Peptides
• RNA, Messenger
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Protein Kinases
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Sirolimus
• Tacrolimus

Topics

• AC133 Antigen
• Antigens, CD (biosynthesis, genetics)
• Cell Line, Tumor
• Chromones (pharmacology)
• Colorectal Neoplasms (genetics, metabolism)
• Down-Regulation (drug effects)
• Glycoproteins (biosynthesis, genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, metabolism)
• Lung Neoplasms (genetics, metabolism)
• Morpholines (pharmacology)
• Neoplasms (genetics, metabolism)
• Peptides (genetics)
• Protein Kinases (metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Signal Transduction
• Sirolimus (pharmacology)
• Stomach Neoplasms (genetics, metabolism)
• TOR Serine-Threonine Kinases
• Tacrolimus (pharmacology)
• Transcription, Genetic
• Up-Regulation (genetics)