FUNCTIONAL ANALYSIS OF Gα15 EXPRESSION IN PANCREATIC CANCER

Pancreatic cancer (PaCa) is the fourth leading cause of cancer death in the USA with overall 5-year survival rate of only 3-5% that leads to an estimated 227000 deaths per year worldwide. To date no effective therapies are available. Surgery is the only potentially curative treatment; however because the majority of lesions are lately diagnosed it results in a palliative treatment in the majority of cases. Therefore, the identification of new factors involved in the tumorigenesis process could help to enlighten the molecular biology of pancreatic cancer and to identify new marker and/or pharmacological target. G15 is a heterotrimeric G protein with its α subunit belonging to the Gαq/11 family. In adult tissues it is selectively expressed in immature cell lineages that feature higher cell renewal potential. It promiscuously couples a wide variety of G protein-coupled receptors (GPCRs) to phospholipase C and shows an exceptional resistance to β-arrestin desensitization. Based on the peculiar characteristics of Gα15, we hypothesized that it might promote tumour growth if expressed out of its natural cell context. Our attention has been drawn toward PaCa since previous results revealed significant expression of Gα15 in human tumour PaCa biopsies xenografted in mice. Here we show that Gα15 is not expressed in normal pancreas. A screening of several PaCa cell lines by TaqMan PCR analysis demonstrated ectopic expression of Gα15 mRNA in a significant subset of cases, as confirmed also by immunoblot. Moreover, Gα15 supports stimulation of PKD1 since its depletion in PaCa cell lines reduced the tonic activation of PKD1. In addition, its depletion dramatically inhibited resistance to the lack of nutrients and anchorage-independent growth. Based on the fact that embryonic endoderm gives rise to the whole digestive tube, Gα15 ectopic expression was investigated also in small intestinal neuroendocrine neoplasia (SI-NENs). The results emerged for PaCa were confirmed also in SI-NENs: only a subset of patient tumour samples and SI-NENs cell lines expressed Gα15 that is absent in normal mucosa and normal enterochromaffin cells. Moreover, a higher Gα15 expression could be predictive of a worse survival. Taken together, our findings suggest that Gα15 supports neoplastic transformation in pancreas and possibly in other organs of the digestive tract and therefore could offer novel potential target for the therapy of PaCa.