This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-1289v1 69/18/7160    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Matsumoto, K. Articles by Nishio, K. PubMed PubMed Citation Articles by Matsumoto, K. Articles by Nishio, K.

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

¹ Department of Genome Biology, ² Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan; and ³ Department of Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

Requests for reprints: Kazuto Nishio, Department of Genome Biology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan. Phone: 81-72-366-0221; Fax: 81-72-366-0206; E-mail: knishio{at}med.kindai.ac.jp.

Key Words: HIF-1 • CD133 • mTOR • rapamycin

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 (HIF-1), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1. Hypoxic conditions up-regulated HIF-1 expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1 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 and HIF-1β were examined using clinical gastric cancer samples. A strong inverse correlation (r = –0.68) was observed between CD133 and HIF-1, but not between CD133 and HIF-1β. In conclusion, these results indicate that HIF-1 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 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. [Cancer Res 2009;69(18):7160–4]