mTOR Signal and Hypoxia-Inducible Factor-1α Regulate CD133 Expression in Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 18; pp. 7160 - 7164
• Main Authors: MATSUMOTO, Kazuko, ARAO, Tokuzo, SAIJO, Nagahiro, NISHIO, Kazuto, TANAKA, Kaoru, KANEDA, Hiroyasu, KUDO, Kanae, FUJITA, Yoshihiko, TAMURA, Daisuke, AOMATSU, Keiichi, TAMURA, Tomohide, YAMADA, Yasuhide
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2009
• Subjects: AC133 Antigen; Antigens, CD - biosynthesis; Antigens, CD - genetics; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Chromones - pharmacology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Down-Regulation - drug effects; Glycoproteins - biosynthesis; Glycoproteins - genetics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medical sciences; Morpholines - pharmacology; Neoplasms - genetics; Neoplasms - metabolism; Peptides - genetics; Pharmacology. Drug treatments; Protein Kinases - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Signal Transduction; Sirolimus - pharmacology; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Tacrolimus - pharmacology; TOR Serine-Threonine Kinases; Transcription, Genetic; Tumors; Up-Regulation - genetics; Signal transduction; Transcription factor HIF1; Gene expression; Tumor cell; Mammalian target of rapamycin
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-1289

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.