Pneumococcal infections and ovarian cancer are two diseases with high incidence and mortality globally. Thus, new insight is required to improve the treatments, diagnoses, and prognoses of these diseases. The PCSK9 enzyme already has a well-established role in cholesterol homeostasis, but its significance in bacterial infections and ovarian cancer is unclear. In her doctoral dissertation, Dafne Jacome Sanz aims to increase our understanding of the role PCSK9 plays in these diseases.
PCSK9 is a secreted protease that modulates cholesterol by decreasing the turn-over of certain lipoprotein receptors via intracellular degradation in the liver. In consequence, the level of circulating lipids increases and eventually accumulates in the blood vessels, which increases the risk of cardiovascular events. Interestingly, PCSK9 links the cholesterol homeostasis with bacterial lipid clearance due to shared pathways and underlying reciprocal mechanisms.
“This year marks two decades of research on PCSK9, a time of extensive clinical and fundamental research. During the time it took to conduct this doctoral research, as many as 2,500 new scientific articles were published on this topic. In the meantime, more than 300 clinical trials have also focused on the usability of PCSK9 inhibitors to treat an array of diseases, including sepsis, which is a leading cause of death due to the complications of the infection,” explains Jacome Sanz.
Potential new findings with therapeutic interest
In her research, Jacome Sanz evaluated the plasma PCSK9 levels of patients with confirmed blood culture-positive infections. She observed that PCSK9 is upregulated upon infection, correlating with other infection markers. The streptococcus pneumoniae bacterium was the organism that upregulated plasma PCSK9 levels the most. She further investigated whether PCSK9 affects the host’s immune responses to pneumococcal infection. To this end, she manipulated the genome of zebrafish with precise gene-editing tools called CRISPR/Cas9 to specifically silence the expression of PCSK9.
The study concluded that in both humans and zebrafish, PCSK9 is upregulated upon systemic infection, resembling an acute-phase protein. Zebrafish do not need PCSK9 for development or surviving pneumococcus. However, its deficiency modified the expression of several immune and lipid metabolism-related genes, suggesting a conserved immunoregulatory function.
Jacome Sanz also studied the putative role of the PCSK9 enzyme in human ovarian cancer cell lines and patient-derived cells. She tested a panel of drugs that could be combined with PCSK9-targeted therapies. When PCSK9 expression was silenced, ovarian cancer cell survival was impaired suggesting a possible anti-apoptotic role. This finding may prove useful for the development of cancer therapies.
“More research is needed to clarify the exact mechanisms of PCSK9 to determine whether PCSK9 plasma levels could be used as an alternative biomarker and for evaluating the use of inhibitors against PCSK9 to treat cancer or sepsis in the future,” Jacome Sanz concludes.
Public defence on Friday 13 October
The doctoral dissertation of M.Sc. Dafne Jacome Sanz in the field of immunoregulation titled Proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme in immunity and cancer will be publicly examined at the Faculty of Medicine and Health Technology of Tampere University at 12 o’clock on Friday 13 October 2023 on the Kauppi campus. The venue is the Yellow Hall (F025) of the Arvo building, address Arvo Ylpön katu 34, Tampere. The Opponent will be Professor Risto Kerkelä from the University of Oulu while Professor Mika Rämet will act as the Custos.