Focal adhesion kinase inhibitor PF573228 and death receptor 5 agonist lexatumumab synergistically induce apoptosis in pancreatic carcinoma.
Pancreatic cancer has one of the lowest survival rates of all cancers. The mechanism underlying chemo-resistance of pancreatic cancer is not well understood. Our previous article reported that small molecule YM155 induced apoptosis in pancreatic cancer cells via activation of death receptor 5. In this study, we aim to continuously address death receptor 5-mediated apoptosis in chemo-resistant pancreatic carcinoma. We found that in comparison to paired pancreatic cancer tissues and adjacent normal tissues, five of the six cancer tissues had downregulated death receptor 5 and upregulated Bcl-xL. Mono treatment with lexatumumab was not sufficient to induce apoptosis in pancreatic cancer cells, whereas focal adhesion kinase inhibitor PF573228 significantly sensitized lexatumumab-induced apoptosis. Western blotting analysis revealed that lexatumumab and PF573228 combination treatment increased death receptor 5 but decreased Bcl-xL expression. Interestingly, pre-treatment with Bcl-xL inhibitor ABT263 reversed the insensitivity of panc-1 cells to lexatumumab or PF573228-induced apoptosis. Specific small interfering RNA-mediated gene silencing of Bcl-xL effectively sensitized pancreatic cancer cells to lexatumumab or PF573228-induced apoptosis. Furthermore, lexatumumab and PF573228 combination was shown to exhibit significant xenograft pancreatic tumor growth inhibition in SCID mice. Our data provide fundamental evidence to support the notion that lexatumumab and PF573228 co-treatment could be a potentially effective regime for patients with pancreatic cancer.
['Zhao|Xiangxuan|X|', 'Sun|Wei|W|', 'Puszyk|William M|WM|', 'Wallet|Shannon|S|', 'Hochwald|Steve|S|', 'Robertson|Keith|K|', 'Liu|Chen|C|']
D000814:Aniline Compounds D000818:Animals D000911:Antibodies, Monoclonal D017209:Apoptosis D045744:Cell Line, Tumor D019008:Drug Resistance, Neoplasm D004357:Drug Synergism D051416:Focal Adhesion Protein-Tyrosine Kinases D015972:Gene Expression Regulation, Neoplastic D006801:Humans D051379:Mice D010190:Pancreatic Neoplasms D015363:Quinolones D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand D013449:Sulfonamides D013450:Sulfones D023041:Xenograft Model Antitumor Assays D051020:bcl-X Protein
focal adhesion kinase PF573228 Lexatumumab apoptosis pancreatic cancer