KRT1853 (prostate and colon cancer xenografts) and IMD-0354 (colon cancer xenograft) suppressed tumor growth is warranted. Of note, IMD-0354 is a known selective IKK inhibitor that is effective in acute and subacute inflammatory disease17, and IMD-0354 did not exhibit substantial inhibitory activity against 102 other kinases at up to 10?M (publicly available data). models. These results strongly recommend KRT1853 for further development as a novel anti-cancer agent. compared with those against cancer cell invasion or viability may be partially due to the low specific activity of recombinant TMPRSS4 serine protease. Next, we evaluated the target selectivity of KRT1853 and IMD-0354 on other proteases. Both compounds failed to substantially inhibit caspase-3 (aspartic protease), cathepsin B (cysteine protease), DPP4, DPP9, FAP (serine proteases), or MMP2 (metalloprotease) protease activities with the exception of DPP4, which displayed an IC50 value of 9.2?M IMD-0354 (Fig.?S3). Rabbit Polyclonal to ERAS These results further confirm that KRT1853 and IMD-0354 selectively target TMPRSS4 at certain levels. Together, these findings suggest that IMD-0354 and KRT1853 suppress TMPRSS4-mediated signaling activity and active uPA level, leading to inhibition of invasion and proliferation as well as the induction of apoptosis. KRT1853 efficiently inhibits tumor growth results. We then examined 2-Deoxy-D-glucose the anti-tumor activity of KRT1853 and IMD-0354 in nude mice bearing TMPRSS4-overexpressing DU145 xenografts. Briefly, cells were injected subcutaneously into the flanks of nude mice. When tumor volumes reached approximately 150?mm3, vehicle or compound (15?g/mouse/time) was intratumorally injected at 3- or 4-day intervals for a total of six times. KRT1853 significantly inhibited tumor growth by 47%, whereas IMD-0354 did not (Fig.?6B). Body weight was not affected by either compound (Fig.?6B). TUNEL staining of tumor sections showed that the level of apoptosis in tumors from mice injected with KRT1853 was higher than that in tumors from mice injected with vehicle although the difference showed marginal statistical significance at the level of value is shown above the graph. (D) HCT116 cells were subcutaneously injected into nude mice (5??106 cells/mouse). On day 15, tumor-bearing mice were randomized into control and treatment groups (n?=?5~6 per group). KRT1853 or 2-Deoxy-D-glucose IMD-0354 were intraperitoneally injected into the mice at intervals of 2 or 3 days for a total of six times. Upper: Tumor volume. Values represent mean??SD. *is warranted. Discussion TMPRSS4, a member of TTSP family, is highly expressed in pancreatic, thyroid, lung, colon, prostate, and other cancers6,10. We previously showed that TMPRSS4 enhances EMT and invasion of colon, prostate, and lung cancer cells12,15. We also reported that TMPRSS4 promotes proliferation of lung and prostate cancer cells via activation of AP-1 and Sp111,12, indicating that TMPRSS4 is positively involved in both proliferation and invasion, although these are not common roles of TTSP family members. Similarly, a recent paper showed that TMPRSS4 promotes thyroid cancer cell proliferation via CREB phosphorylation18. Our previous observation that AP-1 and Sp1 are activated by TMPRSS4 led us to anticipate that TMPRSS4 may modulate cancer cell survival and that inhibition of TMPRSS4 may be an efficient therapeutic strategy for cancer treatment. In this study, we report that TMPRSS4 upregulates bcl-2 and survivin to enhance cancer cell survival, and inhibits anoikis and drug treatment sensitivity, potentially via upregulation of AP-1, Sp1, and NF-B. IMD-0354 and its derivative KRT1853 displayed reduced TMPRSS4-mediated signaling activity, leading to suppression of invasion, proliferation, and survival of cancer cells. KRT1853 (prostate and colon cancer xenografts) and IMD-0354 (colon cancer xenograft) suppressed tumor growth is warranted. Of note, IMD-0354 is a known selective IKK inhibitor that is effective in acute and subacute inflammatory disease17, 2-Deoxy-D-glucose and IMD-0354 did not exhibit substantial inhibitory activity against 102 other kinases at up to 10?M (publicly available data). Therefore, it is probable that IMD-0354 and KRT1853 directly inhibit not only NF-B but also TMPRSS4-mediated signaling activity including AP-1, Sp1, and NF-B 2-Deoxy-D-glucose (indirectly). At present, we cannot explain how selective IKK inhibitor(s), such as IMD-0354, inhibit TMPRSS4 serine protease and related signaling activity. It would be worth investigating the structure of the TMPRSS4 inhibitor-docking protease domain. In terms of drug repositioning, KRT1853 and.
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