Increased expression and cleavage of amyloid precursor-like protein 2 in pancreatic cancer and regulation of fragment stability by major histocompatibility complex class I molecules (165.4)

Abstract

Abstract Particularly in neurological systems, amyloid precursor-like protein 2 (APLP2) has been linked to cellular growth, adhesion and migration. Our laboratory has demonstrated that several human pancreatic cancer cell lines, as well as pancreatic cancer tissue, express a high level of APLP2. Furthermore, we showed that oncogene-induced transformation of pancreatic cells resulted in increased levels of full-length APLP2 and 12-15 kDa APLP2 C-terminal cleavage fragments. Additionally, in pancreatic cancer cell lines we have noted association of APLP2 C-terminal fragments and major histocompatibility complex (MHC) class I molecules, the proteins responsible for the presentation of tumor antigens. The APLP2 C-terminal fragments associated with MHC class I molecules had prolonged stability compared to unassociated fragments. Incubation with calyculin A, which enhances serine/threonine phosphorylation, increased the rate of APLP2 C-terminus turnover. In agreement with our earlier finding, the APLP2 C-termini associated with MHC class I molecules underwent relatively slower degradation in the presence of calyculin A. Thus, MHC class I molecules have a previously unrecognized function of regulating APLP2 homeostasis. Overall, our discoveries have established that APLP2 expression and cleavage are up-regulated in pancreatic cancer, and have led to a new understanding of the involvement of MHC class I molecules in the regulation of APLP2 C-terminal fragments in pancreatic cancer cells.