Abstract 1753: KPNA7, a nuclear transport receptor, promotes malignant properties of pancreatic cancer cellsin vitro.

Pancreatic cancer is an aggressive malignancy and one of the leading causes of cancer deaths. The high mortality rate is mostly due to the lack of appropriate tools for the early detection of the disease and a shortage of effective therapies. We have previously shown that karyopherin alpha 7 (KPNA7) is frequently amplified and overexpressed in pancreatic cancer. KPNA7 is a recently characterized member of the alpha karyopherin family of nuclear import receptors. The nuclear import machinery is composed of a complex network of proteins required for the appropriate transport of proteins from the cytoplasm to the nucleus. Abnormal function of this machinery leads to incorrect localization of nuclear proteins and disturbances in cellular homeostasis, which may subsequently contribute to the development of various diseases including cancer. Indeed, previous evidence has linked members of the karyopherin alpha family, especially KPNA2, to cancer pathogenesis. In this study we demonstrate that KPNA7 expression is absent in practically all normal human adult tissues but elevated in several pancreatic cancer cell lines as well as in some other cancer types. Inhibition of KPNA7 expression in AsPC-1 and Hs700T pancreatic cancer cells led to a striking reduction in cell growth due to the induction of the cell cycle regulator p21 and subsequent G1 arrest of the cell cycle. In both of these cell lines KPNA7 silencing also resulted in decreased anchorage independent growth, and additionally in the AsPC-1 cells reduced cell migration and invasion. Furthermore, in the Hs700T cells KPNA7 silencing resulted in dramatic morphological change where the cells acquired fibroblast-like shape. This phenotypic change was not explained by induction of EMT or senescence. In conclusion, our data strongly demonstrate that KPNA7 silencing inhibits the malignant properties of pancreatic cancer cells in vitro and thereby provide the first evidence on the functional role of KPNA7 in human cancer. Moreover, the lack of KPNA7 expression in normal adult tissues highlights it as a potential novel therapeutic target for cancer. Further studies are needed to identify the cargo proteins transported by KPNA7. These studies are likely to reveal important new information on nuclear transport and may highlight the molecular mechanisms involved in KPNA7 mediated phenotypes in cancer cells. Citation Format: Hanna E. Rauhala, Eeva Laurila, Elisa Vuorinen, Kimmo Savinainen, Anne Kallioniemi. KPNA7, a nuclear transport receptor, promotes malignant properties of pancreatic cancer cells in vitro . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1753. doi:10.1158/1538-7445.AM2013-1753