we selected four pancreatic cancer cell lines that showed differential endogenous expression of PAR 4. We found that nonpeptidic small molecule inhibitors of Bcl 2 family proteins could induce PAR 4 dependent inhibition of cell development and induction of apoptosis. A, down-regulation of Notch 1 by siRNAsignifican tly inhibited BxPC 3 and Co-lo 357 cell growth. TW 37 plus Notch 1 siRNAinhibite n cell growth to a greater degree in contrast to TW 37 alone. W, pancreatic cancer cell death caused by Notch 1 siRNAand Deubiquitinase inhibitor TW 37. . Step 1 siRNA transfected cells were significantly more sensitive to natural and TW 37 induced apoptosis. D, the expression of Notch 1 was detected by Western blotting to test the Notch 1 plasmid transfection efficacy. D, Notch 1 and Hes 1 expression was up regulated by Bcl 2 cDNA. But, Hes 1 expression and Notch 1 was down regulated by Bcl 2 siRNA. Inhibition of Cell Growth by TW 37 To sum up, we presented experimental data that strongly supports the position of TW 37 as an antitumor agent. On the foundation of our results, we suggest a hypothetical pathway by which TW 37 inhibits cell expansion of pancreatic cancer cells, partly mediated through inactivation of Notch 1 and NF nB signaling pathways. But, further in depth studies are essential to see the exact molecular regulation haemopoiesis of Bcl 2, Notch 1, and FoxM1 and their cross talks with NF nB in elucidating the function of TW 37 in cell growth inhibition and apoptosis of pancreatic cancer cells and its antitumor activity in animal models before translating our findings for treating human pancreatic cancer. Disclosure of Potential Conflicts of Interest The University of Michigan has filed a patent on TW 37, which has been licensed by Ascenta Therapeutics, Inc. The University of Michigan and S. Wang own value in Ascenta. S. Wang also acts as a guide for Ascenta Cyclopamine 11-deoxojervine and will be the principal investigator on the research contract from Ascenta towards The University of Michigan. The other authors shared no possible conflicts of interest. Subjective Role of prostate apoptosis response 4 is well described in prostate cancer. Nevertheless, its importance in other cancers has not been fully elucidated. Sensitivity to apoptosis was directly related to the expression levels of PAR 4. However, small interfering RNA against PAR 4 blocked apoptosis, confirming that PAR 4 is really a important player in the apoptotic process. PAR 4 nuclear localization is known as a prerequisite for cells to undergo apoptosis, and we discovered that treating Colo 357 and L3. As confirmed by 4,6 diamidino 2 phenylindole discoloration 6pl cells with 250 nmol/L SMI contributes to nuclear localization of PAR 4. In combination studies with gemcitabine, pretreatment with SMI contributes to sensitization of Colo 357 cells for the apoptotic and growthinhibitory action of a therapeutic drug, gemcitabine.