| Amyloid precursor-like protein 2 (APLP2) is a protein involved in many cellular functions that are aberrant in cancer, such as cell growth, survival, metabolism and immune receptor expression. Ample expression of APLP2 was readily detected in two types of cancer cells, Ewing's sarcoma and pancreatic cancer. Since patients diagnosed with either disease have poor survival rates, novel therapeutics are required. Development of novel therapeutics is improved by a molecular understanding of the cancer cells. Therefore, I investigated oncogenic functions of APLP2 in Ewing's sarcoma and pancreatic cancer cells. I employed cancer cell lines for analysis and used transient transfections to reveal specific functions for APLP2. APLP2 was identified as increasing the tolerance of Ewing's sarcoma cells to radiotherapy. Ewing's sarcoma cells were found to have three subpopulations, characterized by APLP2 surface expression. Following radiotherapy, Ewing's sarcoma cells elevated APLP2 expression at the cell surface and redistributed into higher APLP2 subpopulations; however, cells within the APLP2-high subpopulation were found to have reduced surface expression of MHC class I molecule, an immune receptor, that was not elevated following irradiation. To examine cytotoxic immune recognition of Ewing's sarcoma cells, cell lines were generated that survived co-incubation with an immune effector cell population, lymphokine-activated killer cells. Surviving cells were found to have elevated APLP2 expression. Analysis of the surface expression of immune receptors on these cell lines revealed consistent elevation in MHC class I molecules and reduction in poliovirus receptor (CD155), an activating ligand for natural killer cells. These cell lines were also less sensitive to radiotherapy and proliferated slower in culture. Additionally, APLP2 and its family member, amyloid precursor protein (APP) were found to contribute to the growth of the pancreatic cancer cell line, S2-013. C-terminal cleavage fragments (CTFs) generated by cleavage of APLP2, but not APP, were found across a panel of pancreatic cancer cell lines. Chemical inhibitors of beta-secretase, an enzyme responsible for generating CTFs, reduced the viability of S2-013 cells, but not that of healthy pancreatic ductal cells. Overall, this work sheds light on the oncogenic functions of APLP2 in the context of Ewing's sarcoma and pancreatic cancer. |
