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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.

journal_name

Cancer Res

journal_title

Cancer research

authors

Matsumoto K,Arao T,Tanaka K,Kaneda H,Kudo K,Fujita Y,Tamura D,Aomatsu K,Tamura T,Yamada Y,Saijo N,Nishio K

doi

10.1158/0008-5472.CAN-09-1289

subject

Has Abstract

pub_date

2009-09-15 00:00:00

pages

7160-4

issue

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-09-1289

journal_volume

pub_type

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mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells.