Double inhibition of NF-κB and XIAP via RNAi enhances the sensitivity             of pancreatic cancer cells to gemcitabine.
The majority of patients with pancreatic cancer are resistant to gemcitabine.             One of the mechanisms involved is the anti-apoptotic ability of these cells. The             median lethal dose (LD50) of gemcitabine for PANC-1 cells was higher than that             for Mia PaCa-2 cells and the former had higher nuclear factor-κB (NF-κB) and X-linked             inhibitor of apoptosis protein (XIAP) levels. NF-κB contributes to the inhibition             of apoptosis by the downregulation of downstream genes, such as XIAP and Bcl-2             and it confers chemoresistance. The two cell lines were infected with NF-κB p65             small interfering RNA (siRNA). p65 protein was effectively downregulated accompanied             by the downregulation of XIAP protein. The combination treatment with gemcitabine             and p65 siRNA increased the apoptotic rates in both cell lines; however, this             was not sufficient. XIAP is involved in apoptosis to a greater extent compated             to Bcl-2. XIAP may serve as another factor affecting the sufficiency of chemotherapy.             XIAP siRNA was designed to knockdown XIAP. Mia PaCa-2 and PANC-1 cells were co-infected             with XIAP siRNA and p65 siRNA. XIAP and p65 proteins were effectively downregulated             and the gemcitabine-induced apoptotic rates were significantly increased. These             results suggest that XIAP and NF-κB are two important factors conferring the chemoresistance             of pancreatic cancer cells, and that their downregulation via RNAi effectively             enhances the chemosensitivity of pancreatic cancer cells to gemcitabine.
Department of General Surgery, Xiangya Hospital, Central South University, Hunan 410008, PR China.
Li-Ping
LP
Cao
Jian-Lin
JL
Song
Xiao-Ping
XP
Yi
Yi-Xiong
YX
Li
D017209:Apoptosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*; D000093542:Gemcitabine
D002352:Carrier Proteins; C484020:HSAJ2425 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine