Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:4.1.1.17 (
ornithine decarboxylase
)
6,351
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Proteasomal protein degradation is a promising target for cancer therapy. Here, we developed a positron emission tomography (PET) technique based on the
sodium-iodide symporter
(
NIS
) gene fused with the carboxyl-terminal of
ornithine decarboxylase
(cODC) that noninvasively images cancer cells with inhibited proteasome activity. A retroviral vector was constructed in which the murine cODC degron was fused to the human
NIS
gene (
NIS
-cODC). Transiently transduced CT26 and HT29 colon cancer cells and stably expressing CT26/
NIS
-cODC cells were prepared. In cancer cells transiently transduced with
NIS
-cODC,
NIS
expression and transport activity was low at baseline, but
NIS
protein and
125
I uptake was significantly increased by inhibition of proteasome activity with bortezomib. Stable CT26/
NIS
-cODC cells also showed increased cytosolic and membrane
NIS
by bortezomib, and four different stable clones displayed bortezomib dose-dependent stimulation of
125
I and
99m
Tc-0
4
-
uptake. Importantly, bortezomib dose-dependently suppressed survival of CT26/
NIS
-cODC clones in a manner that closely correlated to the magnitudes of
125
I and
99m
Tc-0
4
-
uptake. CT26/
NIS
-cODC tumors of bortezomib-treated mice demonstrated greater
124
I uptake on PET images and increased
NIS
expression on tissue staining compared to vehicle-injected animals.
NIS
-cODC PET imaging may allow noninvasive quantitative monitoring of proteasome activity in cancer cells treated with bortezomib.
...
PMID:Reporter PET Images Bortezomib Treatment-Mediated Suppression of Cancer Cell Proteasome Activity. 3011 45
We tested the hypothesis that tumor response to conventional bortezomib (BTZ) treatment is enhanced by targeted radiotherapy of resistant cancer stem cells (CSCs) that have characteristically poor proteasome function. This was accomplished by augmenting
131
I uptake through expression of a
sodium-iodide symporter
(
NIS
) fusion protein that accumulates in cells with low proteasome activity. The
NIS
gene fused with the C-terminal of
ornithine decarboxylase
degron (NIS-cODC) was cloned. Stably expressing CT26/
NIS
-cODC cells and tumorsphere-derived CSCs were evaluated for
NIS
expression and radioiodine uptake. CT26/
NIS
-cODC cells implanted into mice underwent PET imaging, and tumor-bearing mice were treated with BTZ alone or with BTZ plus
131
I. CT26/
NIS
-cODC cells accumulated
NIS
protein, which led to high radioiodine uptake when proteasome activity was inhibited or after enrichment for stemness. The cell population that survived BTZ treatment was enriched with CSCs that were susceptible to
131
I treatment, which suppressed stemness features. Positron emission tomography and uptake measurements confirmed high
124
I and
131
I uptake of CT26/
NIS
-cODC CSCs implanted in living mice. In CT26/
NIS
-cODC tumor-bearing mice, whereas BTZ treatment modestly retarded tumor growth and increased stemness markers, combining
131
I therapy suppressed stemness features and achieved greater antitumor effects. The
NIS
-cODC system offer radioiodine-targeted elimination of CSCs that are tolerant to proteasome inhibition therapy.
...
PMID:Targeting poor proteasomal function with radioiodine eliminates CT26 colon cancer stem cells resistant to bortezomib therapy. 3286 72
