Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy.
Pancreatic cancer is one of the most aggressive human tumors with a 5-year survival rate of only 3% and a striking resistance to chemotherapy and radiotherapy. The search for new therapeutic approaches includes strategies exploiting the deregulation of apoptotic pathways commonly found in cancer cells. The IAP proteins are inhibitors of apoptosis that have altered activity in numerous cancer types and are implicated in resistance to chemotherapy, and therefore are potentially interesting as therapeutic targets. We investigated alterations in the expression of IAPs and their inhibitors in pancreatic adenocarcinoma by using real-time PCR, in situ hybridization and immunohistochemistry. We found differential expression of various IAPs in this malignancy, and particularly we observed overexpression of cIAP-2, survivin, livin and XIAP. We also looked for correlations between the expression of IAPs and resistance to paclitaxel, doxorubicin, CDDP and 5-fluorouracil, and found that resistance to these drugs correlates most significantly with expression of cIAP-2. Using RNAi to downregulate these proteins we further confirmed that the levels of cIAP-2 and XIAP influence the response to the anti-cancer drugs, although only marginally for 5-FU. We conclude that anti-tumor strategies based on the inhibition of particular IAPs can be useful in targeting pancreatic adenocarcinoma.
Lopes
Rita Bayer
RB
Centre of Molecular Oncology, Institute of Cancer, Barts and the London School of Medicine, Charterhouse Square, London, UK.
Gangeswaran
Rathi
R
McNeish
Iain A
IA
Wang
Yaohe
Y
Lemoine
Nick R
NR
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D001483:Base Sequence; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism* / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D034622:RNA Interference
D000970:Antineoplastic Agents; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins