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Oncotarget
2016 Aug 02;731:49509-49526. doi: 10.18632/oncotarget.10375.
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SEP enhanced the antitumor activity of 5-fluorouracil by up-regulating NKG2D/MICA and reversed immune suppression via inhibiting ROS and caspase-3 in mice.
Ke M
,
Wang H
,
Zhou Y
,
Li J
,
Liu Y
,
Zhang M
,
Dou J
,
Xi T
,
Shen B
,
Zhou C
.
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Chemotherapy and immunotherapy are the main remedies used in cancer treatment. Because immunotherapy can not only reduce the toxicity of chemotherapeutics but also enhance antitumor effects in vivo, combining these two therapies is a trend that continues to gain more attention in clinic. SEP, a polysaccharide isolated from Strongylocentrotus nudus egg, has been reported to display antitumor activity by stimulating immune cells, including NK and T cells, via TLR2 and TLR4. In the present study, the synergistic effect between SEP and 5-fluorouracil (5-FU), a traditional cytotoxic drug, in vitro and in vivo was investigated. The results obtained indicated that SEP alone stimulated NK-92 cytotoxicity and coordinated with 5-FU to augment the cytotoxicity of NK-92 cells against HepG-2 or A549 cells in vitro. SEP promoted NK-92 activity by stimulating NKG2D and its downstream DAP10/PI3K/Erk signaling pathway. Additionally, 5-FU could increase MICA expression on HepG-2 or A549 cells and prevent membrane MICA from shedding as soluble MICA, which were abrogated in the tumor cells transfected with ADAM 10 overexpression plasmid. Moreover, in H22- or Lewis lung cancer (LLC)-bearing mouse models, SEP reversed 5-FU-induced atrophy and apoptosis in both the spleen and bone marrow in vivo by suppressing ROS generation and caspase-3 activation. All of these results highlight the potential for the combination of SEP and 5-FU in cancer therapy in the future.
Figure 2. SEP-stimulated NK-92 cells are mediated by NKG2D activation(A–B) SEP up-regulates the NKG2D expression on NK-92 cells in a dose- and time-dependent manner. The mean fluorescence intensity in each group is examined using flow cytometry. The histogram overlays shown in panel A are representative of triplicates, and the combined results are presented in panels B. (C–F) SEP activates the expression of DAP10 and the phosphorylation of Akt and Erk in NK-92 cells after 24 h. Densitometric analysis of Erk (D) and the phosphorylation of Akt (E) and DAP10 (F) protein levels in Western blots of NK-92 cells (C). Data are shown as the means ± SD from three separate experiments. *
P < 0.05 and **
P < 0.01 compared with the control group. (G–J) Blocking NKG2D with neutralizing antibody attenuates SEP-activated DAP10 and the phosphorylation of Akt and Erk induced by SEP in NK-92 cells after 24 h. Densitometric analysis of Erk (H), the phosphorylation of Akt (I), and DAP10 (J) protein levels in western blots of NK-92 cells (G). Data are shown as the means ± SD from three separate experiments. *
P < 0.05 and **
P < 0.01 compared with the SEP-treated group. Representative blots are shown from three independent experiments.
Figure 3. 5-FU enhances and maintains the expression of membrane MICA on HepG-2 and A549 cells by preventing ADAM10 expression(A–D) The membrane MICA expression on HepG-2 and A549 cells is enhanced after being exposed to 20 μg/mL of 5-FU for 24 h. The mean fluorescence intensity in each group is examined using flow cytometry. The histogram overlays shown in panels A and C are representative of triplicates, and the combined results are presented in panels B and D. (E–F) 5-FU inhibits sMICA secretion in a dose-dependent manner in the supernatant of HepG-2 (E) and A549 (F) cells after 24 h. (G, I) 5-FU suppresses the protein expression of ADAM10 in HepG-2 (G) and A549 (I) cells in a dose-dependent manner. H, J. Densitometric analysis of ADAM10 protein levels in Western blots of HepG-2 (H) and A549 cells (J). Values are presented as the means ± SD from three separate experiments. **
P < 0.01 compared with the control group. Shown are representative blots from three independent experiments with similar results. (K–L) The increasement of membrane MICA expression on HepG-2 (K) or A549 cells (L) induced by 5-FU is impaired by the overexpression of ADAM10. Tumor cells were divided into ADAM10 group (ADAM10-overexpressed plasmid group), vehicle group (blank-Vector-transfected group) and blank group (no DNA-transfected group), and then incubated with 5-FU (20 μg/mL) for further 24 h. The mean fluorescence intensity in each group is analyzed using flow cytometry. The histogram overlays shown in left panels are the representative of triplicates, and the combined results are presented in right panels. (M–N) ADAM 10 overexpression attenuates 5-FU-suppressed sMICA secretion in the supernatant of HepG-2 (M) and A549 (N) cells was weaken in the ADAM 10 overexpression group. Data are presented as the means ± SD from three separate experiments. **
P < 0.01 compared with the cells in the vehicle group treated with 5-FU.
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