Cancer Chemotherapy, Theoretical Foundations of
183
N(803)
TAD
HIF1
α
bHLH
OH
P(402)
OH
OH
P(564)
VHL
Cul2/
B/C
p300
PAS
Fig. 6
Regulation of the HIFI
α
protein. The domains in HIFI
α
including the basic
helix–loop–helix (bHLH) and PAS domains, required for dimerization and DNA binding
and the C-terminal trans-activation domain are indicated. Hydroxylation of proline (P)
residues at 402 and 564 is required for binding of the von Hippel-Lindau (VHL) tumor
suppressor protein, which recruits an E3 ligase (Cul2/B/C complex) that degrades
HIFI
α
. Hydroxylation of the asparagines (N) residue at 803 in the TAD prevents the
interaction with p300 and downregulates HIF activity.
activity of HIF1 is influenced by the signal
transduction pathway active in the tumor,
and may involve pathways regulated by
insulin, epidermal growth factor, Ras, or
Src. In this respect, VHL is an important
component of HIF1 regulation, and inacti-
vation of VHL tumor suppressor activity in
VHL hereditary cancer syndrome is char-
acterized by a highly restricted cancer pre-
disposition involving renal cell carcinoma,
hemanglioblastoma, and pheochromocy-
toma. In many other tumors, HIF1
α
is
commonly overexpressed, where its lev-
els sometimes correlate with increased
vascular density such as in brain tumors.
In other cases, HIF1
α
overexpression is a
marker for aggressive disease, such as cer-
vical cancer. However, it should be borne
in mind that HIF1
α
is not a universal
marker for clinical outcome. In ovarian
cancer, the overexpression of HIF1
α
with
p53 is correlated with apoptosis, contrast-
ing with the coexpression of HIF1
α
with
mutant p53.
HIF1
α
is gaining increased acceptance
as a potential therapeutic target. The
antitumor effect of some chemotherapeu-
tic agents may be derived from effects
on the HIF1 pathway. For example, ra-
pamycin inhibits hypoxia-induced HIF1
expression, most likely by blocking the
serine/threonine FRAP kinase required
for translation of HIF1 mRNA. Agents
that target other signaling molecules in
the PI3K-AKT-FRAP pathway would sim-
ilarly be expected to alter HIF1 activity
together with many other effects indepen-
dent of HIF1.
To date, mechanism-based therapeutics
that directly target HIF1 are not avail-
able. However, a recent Phase III trial
supports the therapeutic value of agents
that modulate angiogenesis in cancer ther-
apy. The therapeutic antibody, Avastin
TM
,
designed to inhibit VEGF activity, which
plays a critical role in tumor angiogen-
esis, provided a 50% increase in pa-
tient survival chance compared to patients
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