Proteolysis-inducing factor differentially influences transcriptional regulation in endothelial subtypes

Abstract

Proteolysis-inducing factor (PIF) is a novel sulfated glycoprotein initially identified as a protein capable of triggering muscle proteolysis during the process of cancer cachexia. Only skeletal muscle and liver exhibit substantial binding of PIF in adult tissue. Here, we demonstrate that PIF induces transcriptional regulation in both the liver endothelial cell line SK-HEP-1 and in human umbilical vein endothelial cells (HUVECs) but not in pulmonary artery endothelial cells. PIF differentially induces activation of nuclear factor-κB, resulting in the induction of proinflammatory cytokines [interleukin (IL)-8 and IL-6] and increased expression of the cell surface proteins intercellular adhesion molecule-1 and vascular cell adhesion molecule in SK-HEP-1 and HUVECs only. In addition, PIF induces the shedding of syndecans from the cell surface. Syndecans are involved in wound repair, metastasis of cancers, and embryonic development. These results suggest that PIF may play additional roles in the proinflammatory response observed in cancer cachexia but may also have a role without the cachectic process.

Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues

“…This may be essential to its function as a cachetic factor, as dermcidin expression does not appear sufficient to induce cachexia (Monitto et al, 2004). Similarly, deglycosylated PIF lacks proteolytic activity in murine gastrocnemius muscle (Todorov et al, 1996(Todorov et al, , 1997, and in our experiments it was the fully glycosylated PIF molecule that influenced hepatic cell NF-kB and STAT3 activity and gene expression (Watchorn et al, 2001(Watchorn et al, , 2002. However, the PIF aminoacid sequence lacks typical consensus N-and O-glycosylation sites and the mechanism of glycosylation remains unknown.…”

“…In primary hepatocytes and HepG2 cells, PIF was found to activate the transcription factors NF-kB and STAT3, resulting in the stimulation of IL-8, IL-6 and CRP production, and the inhibition of transferrin production (Watchorn et al, 2001). Proteolysis-inducing factor was also found to induce the expression of NF-kB, IL-6, IL-8, ICAM-1 and VCAM and the shedding of syndecans in the liver endothelial cell line SK-HEP-1 and human umbilical vein endothelial cells, but not in pulmonary artery endothelial cells (Watchorn et al, 2002). These results are consistent with a role as a cachectic factor.…”

Mechanisms of Cancer Cachexia

“…Using recombinant human PIF, both a human liver endothelial cell line and umbilical vein endothelial cell line responded by the release of increased amounts of IL-6 and IL-8 (274), and this may contribute to the APR seen in cachexia. The effect occurs through the NFB and STAT3 transcriptional pathways.…”

Tumor Secreted Autocrine Motility Factor (AMF): Causal Role in an Animal Model of Cachexia

“…Chlamydial infection, for example, may contribute to cachexia in patients with AIDS, and in general patients with cachexia are immunocompromised. Recent works shows that PIF can activate, through NF-6B, endothelial cell expression of IL-6 and IL-8 (Watchom et al, 2002), the later of which is produced by breast cancer cells and can directly enhance bone metastases (Bendre et al, 2002).…”