Members Members Residents Residents Corner
Join Today Renew Your Membership Make A Donation
2001 Abstract: 564 PI-3'Kinase and NF-kB Induced Chemoresistance in Human Pancreatic Cancer

2001 Digestive Disease Week

# 564 PI-3'Kinase and NF-kB Induced Chemoresistance in Human Pancreatic Cancer
Shimul A. Shah, Michael W. Potter, Mohir H. Hedeshian, Mark P. Callery, Worcester, MA

Introduction: Since TNF-a and some chemotherapeutic agents activate both apoptosis and NF-kB dependent anti-apoptotic genes, they may neutralize their own anti-tumor effects. The cell signaling mechanisms for such chemoresistance are not clear, but may involve PI-3'Kinase (PI3K). To clarify this, we examined whether cross-signaling between PI3K and NF-kB enhances the anti-tumor effect of TNF-a in human pancreatic cancer cells.

Methods: Quiescent pancreatic cancer cells (Panc-1, MiaPaCa-2)with TNF-a, Ly294002 (PI3K inhibitor), alone or combined, were restimulated with mitogen (10% FCS) to induce cell cycle entry. Proliferation (MTT), cell cycle progression (ApoBrDU incorporation and FACS analysis), and apoptosis (PARP cleavage; caspase-3 activation - Western blot [WB])were measured. Akt activation (Akt kinase assay) and IkBa degradation were determined by WB. Translocation of NF-kB into the nucleus was examined by EMSA, while a NF-kB/luciferase reporter gene was used to quantify NF-kB dependent gene expression. Statistical analysis - two-tailed t-test (p<0.05).

Results: PI3K inhibition significantly enhanced the anti-proliferative and pro-apoptotic effects of TNF-a in both cell lines, but only after arresting cells in G0-G1 phase. Ly294002 also blocked TNF-a-induced Akt activation, but failed to alter cytoplasmic IkBa degradation or subsequent NF-kB nuclear translocation. NF-kB dependent gene expression, however, was ultimately suppressed by Ly294002 (Fig 1), suggesting that PI3K-dependent activation of NF-kB is IkBa-independent.

Conclusions: PI3K inhibition can block NF-kB dependent gene expression regardless of cytoplasmic IkBa/NF-kB activation. Since it also regulates the anti-tumor effects of TNF-a, PI3K may in part determine NF-kB induced chemoresistance in human pancreatic cancer.

Society for Surgery of the Alimentary Tract

Facebook Twitter YouTube

Email AAPS Email AAPS
500 Cummings Center, Suite 4400, Beverly, MA 01915 500 Cummings Center
Suite 4400
Beverly, MA 01915
+1 978-927-8330 +1 978-927-8330
+1 978-524-0498 +1 978-524-0498
Annual Meeting
Make a Pledge
Event Calendar