Abstract
Because tumor necrosis factor-alpha (TNF-α) and some chemotherapeutic agents activate both apoptosis andNF-κB-dependent antiapoptotic genes, they may neutralize their own antitnmor effects. The cell-signaling mechanisms for such chemoresistance are not clear but may involve phosphotidylinositol 3′ kinase (PI3K). To clarify this we examined whether cross-signaling between PI3K and NF-κ B enhances the antitnmor effect of TNF-α in human pancreatic cancer cells. Quiescent pancreatic cancer cells (Pant-1, MiaPaCa-2) with TNF-α, Ly294002 (PI3K inhibitor), alone or combined, were restimulated with mitogen (10% fetal calf serum [FCS] to induce cell cycle entry). Proliferation (monotetrazolium), cell cycle progression (ApoBrDU and fluorescence-activated cell sorter analysis), and apoptosis (PARP cleavage; caspase-3 activation) were measured. Akt activation (Akt kinase assay) and IKB~ degradation were determined by Western blot analysis. Translocation of NF-κ B into the nucleus was examined by EMSA, whereas an NF-κ B/hiciferase reporter gene was used to quantify NF-κ B-dependent gene expression. Statistical analysis was carried out by means of two-tailed t test (P <0.05). PI3K inhibition significantly enhanced the antiproliferative and proapoptotic effects of TNF-α in both cell lines. Ly294002 also blocked TNF-α -induced Akt activation but failed to alter cytoplasmic IκBα degradation or subsequent NF-κ B nuclear translocation. NF-κ B-dependent gene expression, however, was ultimately suppressed by Ly294002, suggesting that PI3k-dependent activation of NF-κ B is Iκ Bα independent. PI3K inhibition can block NF-κ B-dependent gene expression regardless of cytoplasmic IKBNF-κ B activation. Because it also regulates the antitumor effects of TNF-α PI3K may in part determine NF-κ B-induced chemoresistance in human pancreatic cancer.
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Shah, S.A., Potter, M.W., Hedeshian, M.H. et al. PI-3’ kinase and NF-ΚB cross-signaling in human pancreatic cancer cells. J Gastrointest Surg 5, 603–613 (2001). https://doi.org/10.1016/S1091-255X(01)80102-5
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DOI: https://doi.org/10.1016/S1091-255X(01)80102-5