Abstracts
1997 Digestive Disease Week

Growth inhibition in pancreatic tumor cells by targeting a cyclin-dependent kinase inhibitor.

IA Mustafa, MP Vezeridis, HJ Wanebo, S Sharma. Department of Surgery, Brown University/Roger Williams Medical Center, Providence, RI.

Pancreatic cancer is the fourth leading cause of cancer death for men and the fifth for women, yet the molecular basis of pancreatic tumorigenesis is currently poorly understood. This has resulted in suboptimal therapy and a generally dismal prognosis. Work from our laboratory and others has suggested that tumor cells become resistant to mitogenic signals such as transforming growth factor beta (TGF-ß). In cells of epithelial origin, this factor has a growth inhibitory effect via regulation of reversible arrest in the G1 phase of the cell cycle. Here we show that a group of pancreatic tumor cell lines representing both aggressive metastatic potential (FG and L3.4) as well as poor metastatic potential (SG) fail to respond to TGF-ß. Under normal circumstances, TGF-ß exerts its inhibitory effects via signal transduction pathways which involve cyclin kinase inhibitors. In an attempt to understand cell cycle aberrations in these cell lines, we have focused on the cyclin D/cdk4 and cyclin E/cdk2 kinase inhibitor p27^kip1. Our data suggest that these pancreatic tumor cell lines, irrespective of their cell cycle stage, fail to significantly express p27^kip1. TGF-ß1 or rapamycin, an immunosuppressant, which are known to activate p27^kip1 functions, fail to inhibit the growth of these pancreatic tumor cell lines. In addition, they do not restore p27^kip1 levels. On the other hand, LLnL (N-Acetyl-Leu-Leu-Norleucinal) a proteasome inhibitor which has been shown to protect p27^kip1 from ubiquitin-mediated proteolysis, exhibited a dose-dependent growth inhibitory effect in both the highly metastatic and less metastatic cell lines. Ubiquination of p27^kip1 by proteolytic enzymes may be important in appropriate timing of cell cycle signaling events as cells progress through their cycle. These data will be further discussed in the context of increasing the threshold p27^kip1 levels and pRb dephosphorylation, thus defining one mechanism of escape from normal growth control. [Figure not available.]