Abstract
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 131I 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 131I. 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 131I treatment, which suppressed stemness features. Positron emission tomography and uptake measurements confirmed high 124I and 131I 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 131I 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.
Highlights
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
125I uptake was low in CT26/NIS-cODC cells at baseline but was substantially increased to 332.0 ± 29.8% of controls in the presence of BTZ (P < 0.001; Fig. 1B)
Tumorsphere-derived CT26/NIS-cODC cells displayed a complete abrogation of proteasome activity (Fig. 2B) and a 4.6 ± 0.1-fold increase of CD133 expression compared with monolayer-grown cells (P < 0.001; Fig. 2A), indicating enrichment for CSCs
Summary
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 131I uptake through expression of a sodium-iodide symporter (NIS) fusion protein that accumulates in cells with low proteasome activity. After cytotoxic drugs succeed in eliminating the bulk of the tumor, the limit of their effectiveness is met, and the surviving population propagates to drive cancer r elapse[1] Crucial contributors to this phenomenon are cancer cells with stemness properties that have preferential resistance to chemotherapeutics[2,3]. The clinical efficacy of proteasome inhibitors to treat solid tumors has been disappointing far[17]
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