CD147 Regulates Cell Metabolism in Pancreatic Cancer via Targeting of Multiple Small Molecule Transporters to the Cell Membrane

Abstract

CD147 is a highly glycosylated type I transmembrane protein upregulated in pancreatic cancer where it has received significant attention as a potential therapeutic target due to its regulation of several proteins that drive cancer progression. While CD147 was initially thought to act as a ligand on the cell surface to directly stimulate the secretion of several proteins, recent findings have suggested that CD147 may contribute to cancer progression through a much more complex set of interactions. The present study identified CD147 as having a unique chaperone role for multiple transmembrane proteins important for signaling events related to cancer metastasis and metabolic maintenance in pancreatic cancer. A robust combination of cellular, biochemical, proteomic and metabolomic studies showed that CD147 depletion leads to a significant decline in cell proliferation and migration, an increase in epithelial phenotype, and a striking reprogramming of cellular metabolism. Xenograft mouse models further confirmed these findings where tumor growth and metabolism were dependent on CD147 expression. In order to determine the underlying mechanism of CD147's role in pancreatic cancer, we combined crosslinking methods with mass spectrometry to identify the specific interactions and discovered that CD147 is responsible for targeting multiple transmembrane proteins to the cell surface. Furthermore, CD147 depletion caused a down-regulation of a subset of these proteins, which could then be reversed with proteosomal inhibitor treatment indicating that CD147 is a chaperone. Together, our studies illustrate the functional consequence of CD147 expression and chaperone activity in relation to regulating pancreatic cancer progression.