br Moreover it is worth
Moreover, it is worth mentioning that our data showed incon-sistent changes in AKR1B10 expression at the mRNA and protein levels, which indicate there might be an epigenetic modification of AKR1B10, since metastatic microenvironments largely con-tribute to molecular epigenetic changes in tumor cells. Recent studies suggest an undervalued role of post-transcriptional, trans-lational, and degradation regulations in the determination of pro-tein concentrations, and these regulations contribute at least as much as transcription itself [57–60]. In the last decade, it has been reported that S-nitrosylation was a post-translational mechanism that regulated the AR superfamily [61,62]. S-nitrosylation, the oxidative modification of Cys residues by nitric oxide (NO) to form S-nitrosothiols (SNOs), provides a fundamental redox-based cellu-lar signaling mechanism and regulates protein activity, stability, localization, and protein–protein interactions in a wide range of biological processes [63,64]. AR was thiol-modified by NO at the active-site residual Cys-298, which is considered the main site of modification, and this resulted in the changes of AR characteristics like protein stability and catalytic activity . In view of the knowledge that metastatic lung cancer Brefeldin A face a cascade of oxidative stress during BM and NO is induced by oxidative stress as the ubiquitous second messenger, we hypothesize that AKRIB10 undergoes post-translational S-nitrosylation during BM, which causes an increase in protein stability and a subsequent increase in protein concentrations in metastasized tumors. However, fur-ther well-designed and in-depth studies are warranted.
In summary, we built a multi-organ microfluidic bionic chip platform to study lung cancer BM, and verified its effectiveness using lung cancer cells with differing metastatic abilities. Our study also demonstrated that AKR1B10 was significantly elevated in lung cancer-derived BM. AKR1B10 promoted the disassembly of the BBB to facilitate the trans-endothelial migration of tumor cells, possibly by up-regulating MMP-2 and MMP-9 expression mediated by a MEK/ERK signaling pathway.
WWL and JS conceived all aspects of this study, chip design and set-up, animal studies, participated in all other experiments and prepared the manuscript. XHD, YZ and YL assisted with the design and fabrication of chip. RL assisted with q-PCR, western blot, enzyme-linked immunosorbent assay. LL and YTH assisted with collection of clinical specimens. JXH and JB assisted with immunofluorescence assays and cell culture studied. HBS, WW and QW designed and supervised the experiment.
Conflicts of interest
There are no conflicts to declare.
Appendix A. Supplementary data
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AKT1-targeted proapoptotic activity of compound K in human breast cancer cells
Eunju Choi, Eunji Kim, Ji Hye Kim, Keejung Yoon, Sunggyu Kim, Jongsung Lee, Jae Youl Cho
To appear in:
Journal of Ginseng Research
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