Targeting the RNA splicing machinery as a novel treatment strategy for pancreatic carcinoma.
Aberrant patterns of pre-mRNA splicing have been established for many human malignancies, yet the mechanisms responsible for these tumor-specific changes remain undefined and represent a promising area for therapeutic intervention. Using immunohistochemistry, we have localized the expression of a central splicing regulator, serine-arginine protein kinase 1 (SRPK1), to the ductular epithelial cells within human pancreas and have further shown its increased expression in tumors of the pancreas, breast, and colon. Small interfering RNA-mediated down-regulation of SRPK1 in pancreatic tumor cell lines resulted in a dose-dependent decrease in proliferative capacity and increase in apoptotic potential. Coordinately, the disruption of SRPK1 expression resulted in enhanced sensitivity of tumor cells to killing by gemcitabine and/or cisplatin. A dose-dependent reduction in the phosphorylation status of specific SR proteins was detected following the down-regulation of SRPK1 and is likely responsible for the observed alterations in expression of proteins associated with apoptosis and multidrug resistance. These data support SRPK1 as a new, potential target for the treatment of pancreatic ductular cancer that at present remains largely unresponsive to conventional therapies. Furthermore, these results support the development of innovative therapies that target not only specific splice variants arising during tumorigenesis but also the splice regulatory machinery that itself may be abnormal in malignant cells.
Mayo Clinic Cancer Center and Department of Molecular Pharmacology and Experimental Therapeutics, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
Gregory M
GM
Hayes
Patricia E
PE
Carrigan
Alison M
AM
Beck
Laurence J
LJ
Miller
D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D000093542:Gemcitabine
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D003841:Deoxycytidine; C087728:SRPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin; D000093542:Gemcitabine