These results suggest that the PI-3K/AKT pathway plays a pivotal role in the pathogenesis of pancreatic cancer and ARHI exerts its growth-inhibitory effects through modulation of several key G1 regulatory proteins, such as p21WAF1, p27kip1, CDK2, CDK4 and cyclins A and D1.
Three known tumor suppressor genes, p16/CDKN2, BRCA2, and p53, all of which are important in the development of pancreatic carcinoma and frequently are involved in a variety of cancer syndromes, were analyzed.
The p16(INK4a) (MTS-1, CDKN2) gene product acts in the same pathway as p53 to inhibit cell cycle progression at G1/S. p16(INK4a) is deleted and/or mutated in a significant fraction of human tumors, including pancreatic carcinoma.
These findings suggest that, although p16/CDKN2 may play a role in the pathobiology of pancreatic cancer, inactivation of this putative tumor suppressor gene occurs more frequently in cell lines than in primary ductal pancreatic carcinomas.
Loss of heterozygosity studies in melanoma and pancreatic carcinoma from gene carriers strongly support the view that CDKN2 is a general tumour suppressor gene predisposing not only to melanoma but also to other malignancies.