Key Role of Phosphoinositide 3-Kinase Class IB in Pancreatic Cancer

Purpose: Phosphoinositide 3-kinase (PI3K) signaling is well established as important in cancer. To date most studies have been focused on the PI3K/p110 alpha isoform, which has been found to be mutated in several different cancers. The aim of our study was to determine which specific PI3K isoforms are involved in pancreatic ductal adenocarcinoma (PDAC) and investigate the effects of these isoforms on proliferation, survival, and induction of Akt activation in pancreatic cancer cells. Experimental Design: The expression of all PI3K isoforms and downstream targets was analyzed by immunohistochemistry in human pancreatic cancer tissue and normal counterparts. Isoform selective inhibitors and short interfering RNA (siRNA) were employed to investigate the effects of the different PI3Ks on proliferation, survival, and intracellular signaling in PDAC cell lines. Results: Immunohistochemical screening revealed high specific expression of the PI3K/p110 gamma isoform. Scoring indicated that 72% of the PDAC tissue stained positive for PI3K/p110 gamma, whereas no stain was detected in normal pancreatic ducts. Proliferation analyses after selective inhibition and siRNA downregulation of PI3K/p110 gamma showed that PI3K/p110 gamma, but not other PI3K isoforms, was required for cell proliferation. Overexpression of PI3K/p110 gamma indeed increased cell numbers and mediated activation of Akt in PDAC cell lines. Moreover, PI3K/p110 gamma was required for Akt activation via lysophosphatidic acid receptors. Conclusions: These data represent the first identification of a tumor-specific accumulation of the PI3K isoform p110 gamma in human cancer. Further, our results signify a critical role for PI3K/p110 gamma in pancreatic cancer, and we hypothesize that PI3K/p110 gamma overexpression is a key event in the disease progression. Clin Cancer Res; 16(20); 4928-37. (C) 2010 AACR.