Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) Enzyme in Immunity and Cancer

The first and best characterized physiological function of PCSK9 enzyme has been the regulation of the low-density lipoprotein receptors (LDLR) turn-over in the liver, affecting the circulating cholesterol uptake, and contributing eventually to the development of cardiovascular events. Recently it has been reported that PCSK9 controls the turn-over of other cellular receptors, such as the major histocompatibility complex class I (MHC-I). However, its participation in the immune responses against infections and cancer, is not fully understood, in part, due to the diverse results obtained in bacterial infections studies, and in part because little research has been done in certain malignancies with altered lipid metabolism, such ovarian cancer.

In the present study, circulating PCSK9 protein levels were explored in bacteremic patients. Interestingly, those with lower PCSK9 levels, but still over the normal range, had worse prognosis. Thus, to study in vivo the effects of PCSK9 gene knockout upon pneumococcal infection, two zebrafish mutant lines were generated using a genetic modification method called CRISPR/Cas9. Both, in humans and zebrafish, PCSK9 gene and protein levels are upregulated upon systemic infection, especially due to Streptococcus pneumoniae, where it resembles an acute-phase reactant correlating with the levels of infection-associated marker C-reactive protein (CRP). In zebrafish, PCSK9 protein is dispensable for the correct neurogenesis during ontogeny, and also for adult host survival against Streptococcus pneumoniae infections. However, certain immune related genes were downregulated, whereas lipid- metabolism related genes were upregulated, suggesting a conserved hepatic immunoregulatory function.

Lastly, the expression and putative role of PCSK9 protein in epithelial ovarian cancer cells was explored in selected cell lines. It was found that PCSK9 protein is expressed and secreted by immortalized cell lines and patient derived cancer cell cultures, suggesting a paracrine modulation. PCSK9 protein was also detected at low concentrations in patients’ ascites fluids. Furthermore, to study its effects on cell proliferation, PCSK9 gene expression was modulated. When PCSK9 gene was silenced, cancer cell survival was impaired, suggesting a pro-survival role for PCSK9 protein, in line with previous studies in other malignancies. When PCSK9 protein expression was transiently induced, intracellular signaling activation was observed, reinforcing the pro-survival role for PCSK9.

In conclusion, PCSK9 plays a role in immunity and cancer. However, some aspects remain ambiguous, and more research would be needed to determine its roles and its usefulness as a therapeutic target to treat bacterial infections or cancer.