CD44/Hyaluronan signaling in advanced prostate cancer is associated with hyper-activation of eIF4E mediated translation.

Abstract

One microenvironment alteration during prostate tumor progression involves changes in synthesis of the extracellular matrix component hyaluronan (HA). HA is a high molecular weight anionic polysaccharide that increases in tumors and is important for facilitating tumor growth and progression. CD44 is a transmembrane type 1 cell surface receptor that binds to hyaluronan and activates multiple downstream pathways associated with tumor growth and invasion. A major phenotypic change associated with malignant progression of carcinomas involves abnormalities in regulation of translation driven by the initiation complex eIF4F which recognizes the m7GpppN cap structure on the 5’-end of mRNA. Subsets of mRNAs most affected by eIF4F-mediated control are those encoding proteins that promote abnormal proliferation, survival and malignant progression. This study assessed if HA/CD44 signaling promoted hyperactivation of eIF4F-dependent translation. We first established that highly metastatic prostate cancer cells depend on high levels of CD44 to promote cell proliferation, cell cycle progression and anchorage independent cell growth. We next used several cell lines to determine that activity status of the eIF4F complex increases as a function of malignant potential. Translation profiling identified a subset of carcinoma-associated mRNAs differentially recruited into polyribosomes in a manner dependent on levels of CD44. The data show that CD44 signaling robustly stimulates the translational efficiency of mRNAs encoding the crucial cell cycle promoters Cyclin D1 and c-Myc, both of which are associated with metastatic prostate cancer. This increased translation of Cyclin D1 and c-Myc are associated with a shortened cell cycle, which may be important for increasing tumor burden in cancer patients.