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Department of Cell and Cancer Biology (M.G., A.M., S.L., R.P.,
W.G.A., L.N., J.T., F.C.) National Cancer Institute National
Institutes of Health Bethesda, Maryland 20892
Department
of Histology and Pathology (L.M.M.) University of Navarra 31080
Pamplona, Spain
Department of Biology (H.R., R.J.)
University of California San Diego La Jolla, California 92093
Institute of Physiology (M.G.) University of
Zürich-Irchel CH-8057, Switzerland
Little is known about the molecular mechanisms
that control adrenomedullin (AM) production in human cancers. We
demonstrate here that the expression of AM mRNA in a variety of human
tumor cell lines is highly induced in a time-dependent manner by
reduced oxygen tension (1% O2) or exposure to
hypoxia mimetics such as desferrioxamine mesylate (DFX) or
CoCl2. This AM expression seems to be under
hypoxia-inducible factor-1 (HIF-1) transcriptional regulation, since
HIF-1
and HIF-1ß knockout mouse cell lines had an ablated or
greatly reduced hypoxia AM mRNA induction. Similarly, inhibition or
enhancement of HIF-1 activity in human tumor cells showed an analogous
modulation of AM mRNA. Under hypoxic conditions, immunohistochemical
analysis of tumor cell lines revealed elevated levels of AM and
HIF-1 as compared with normoxia, and we also found an increase
of immunoreactive AM in the conditioned medium of tumor cells analyzed
by RIA. AM mRNA stabilization was shown to be partially responsible for
the hypoxic up-regulated expression of AM. In addition, we have
identified several putative hypoxia response elements (HREs) in the
human AM gene, and reporter studies with selected HREs were capable of
enhancing luciferase expression after exposure to DFX. Furthermore,
transient coexpression of HIF-1 resulted in an augmented
transactivation of the reporter gene after DFX treatment. Given that
most solid human tumors have focal hypoxic areas and that AM functions
as a mitogen, angiogenic factor, and apoptosis-survival factor, our
findings implicate the HIF-1/AM link as a possible promotion mechanism
of carcinogenesis.
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