Key takeaways:
~ PCSK9 is an enzyme that helps regulate cholesterol levels by reducing LDL receptor uptake in the liver. It also affects the immune system, interacting with MHC I and reducing LRP1 levels.
~ In several types of cancer, lower PCSK9 levels are associated with a reduced risk of cancer metastasis.
~ Animal studies show that inhibition of PCSK9 can reduce metastasis in several types of cancer.
~ Genetic studies show that higher PCSK9 levels correlate with a higher rate of breast cancer recurrence (22%) while genetically lower PCSK9 levels were associated with a lower rate of breast cancer recurrence (2%).
PCSK9: More than just cholesterol levels
PCSK9 (Proprotein convertase subtilisin/kexin type 9) is best known for its role in regulating cholesterol levels in the body. More recently, however, researchers have discovered that it also plays an important role in regulating the immune response. This has led to discoveries about how PCSK9 levels affect the risk of cancer metastasis or recurrence.
PCSK9 is a protease that can break apart certain proteins in the body. It plays an important role in regulating the levels of several different proteins that act as receptors. It’s like a Swiss army knife with multiple functions for regulating levels of cholesterol, certain immune system proteins, and other cell surface receptors.
Before we get into the new studies on preventing cancer recurrence, let’s look at some of the different roles PCSK9 plays in the body.
LDL receptor availability:
Cholesterol is an essential component of cell membranes and is used in the biosynthesis of steroid hormones (e.g., testosterone, estrogen). The body tightly regulates cholesterol levels through several mechanisms, one of which is PCSK9.
LDL receptors in liver cells take up cholesterol and remove it so that it doesn’t circulate in the body. The availability of these LDL receptors then plays a big role in how much cholesterol is in the bloodstream.
The PCSK9 protein triggers LDL-receptor degradation in the liver, resulting in higher circulating levels of LDL. The uptake of cholesterol in the liver is one of the main ways that the body regulates cholesterol levels, and PCSK9 levels are key to how much cholesterol is taken up by liver cells.[ref]
People with PCSK9 gain-of-function mutations have elevated cholesterol levels due to the liver not taking up as much cholesterol (not as many LDL receptors). Variants that reduce PCSK9 function cause lower lifelong LDL cholesterol levels because more of it is taken up in the liver. These genetic discoveries led to the creation of PCSK9 inhibitor drugs that can decrease high cholesterol.
MHC I (HLA):
Major histocompatibility complex class I (MHC I) proteins are on the surface of almost all cells and present peptides to help the immune system identify and respond to infections. Essentially the MHC class I proteins — also called HLA — bring peptides from inside the cell to the cell surface so that the circulating immune system T cells will know if there is anything ‘bad’ in the cell, such as a virus or bacteria.
Similar to the way that PCSK9 causes LDL receptors to not be able to be on the surface of liver cells, PCSK9 can also disrupt the recycling of MHC I proteins to the surface of cells.[ref] Thus – more PCSK9 can result in fewer MHC I proteins on the surface of cells.
This could be important in cancer because MHC I proteins also present molecules that are normally found within the cell so that the immune system can identify them as normal cells. When there is a cancerous mutation, the molecules presented on the surface of the cell should trigger the immune system to kill the cell. You want a strong immune system to kill off cells that aren’t right.
With more PCSK9 causing fewer MHC I proteins recycled to the cell membrane, this means that the immune system will be a little less likely to recognize that a cell is cancerous and kill it off. The opposite is also true – less PCSK9 means more MHC I proteins presenting pieces of the cell to the immune system. In the context of the new types of cancer immune therapy, animal and cell studies show that therapies using the immune system to combat cancer, such as checkpoint inhibitors, work better when PCSK9 levels are lower.[ref]
LRP-1 receptor:
Low-density lipoprotein receptor-related protein 1 (LRP1) is another cell surface receptor that interacts with PCSK9. Similarly to the LDL receptor, PCSK9 can also induce the degradation of LRP1. [ref]
The LRP1 receptor is an endocytic receptor. This means that other molecules can dock with it on the cell surface and then be taken into the cell via endocytosis.
LRP1 plays a role in insulin signaling, inflammation, bone remodeling, and lipoprotein metabolism (e.g. APOE). It also interacts with ADAMTS4, ADAMTS5, MMP13, PAI-1, and TIMP2. In development, it plays an essential role in the formation of bones and the heart.[ref] LRP1 is also a regulator of tau protein uptake in the brain and clearance of amyloid beta across the blood-brain barrier.[ref][ref]
LRP1 also interacts with cancer metastasis, repressing the ability of circulating cancer cells to adhere to the extracellular matrix. A new study shows that higher serum PCSK9 results in lower LRP1, which then allows for easier metastasis of breast cancer.[ref]
Going a little deeper into the PCSK9 function
PCSK9 is a serine protease, which means that it is an enzyme that can break apart proteins (for example, the LDL receptor protein). Serine proteases are a class of proteolytic enzymes that have a serine amino acid molecule at the active site
In addition to the main function of degrading the LDL receptor in liver cells, PCSK9 is also involved in pancreatic function, immune regulation, and viral activation.
In addition to directly affecting MHC I presentation on cell surfaces, PCSK9 also regulates inflammatory cytokine levels by activating TLR4 and NFkB. Lower PCSK9 reduces the expression of inflammatory cytokines.[ref] Similarly to the LDL receptor, PCSK9 also degrades CD36, which is a fatty acid transporter as well as a modulator of the immune response.[ref]
In the pancreas, PCSK9 is expressed in the pancreatic islet B-cells that produce insulin. While deleting PCSK9 doesn’t have an effect on insulin secretion, an increase in insulin causes increased expression of PCSK9.[ref] Studies show that lower PCSK9 can increase the risk of type 2 diabetes.[ref][ref]
Pathogens and PCSK9: Tradeoffs for survival
A recurring theme in genetic research is that many of the common genetic variants that cause problems in our modern world are in the genome because they were beneficial for the survival of our ancestors. The main mortality factor shaping our genome was surviving pathogens – the plague, cholera, malaria, leprosy, tuberculosis, and various viruses that caused fever.
PCSK9 interacts with different pathogens in different ways. Some pathogens, such as the dengue virus, use PCSK9’s ability to target the LDL receptor as a way of enhancing their ability to infect cells. Conversely, hepatitis C infection will decrease PCSK9 and LDLR levels. Circulating PCSK9 can also reduce the levels of CD36, which is a fatty acid transporter. CD36 is also key in the immune response to malaria. Researchers think the connection between CD36 and malaria has been a driving factor for some of the genetic variants that increase PCSK9 levels. For example, someone with a variant that increased PCSK9 levels a bit may be more likely to survive malaria — and pass on the variant to their offspring.[ref][ref]
PCSK9 Levels and Cancer:
Note: This is an ongoing field of research with more to be discovered. What is presented here is likely just the tip of the iceberg in terms of research still to come.
There has been quite a bit of research in the last five years or so looking at how PCSK9 levels interact with cancer risk and, more recently, the risk of cancer metastasis or recurrence. Some of the early studies looked at PCSK9 from the point of view that lower cholesterol levels might be beneficial for reducing the rate of cell growth in cancer. More recent studies are also taking into account MHC class I protein signaling and the ability of the host immune system to kill cancer cells[ref] Studies also show that the tumor microenvironment may be different from the circulating PCSK9 levels.[ref] Overall, a picture is emerging that lower PCSK9 levels allow more of a CD8+ T cell response against tumor cells. This could mean that the immune system is more likely to kill off cancer cells that escape and cause metastasis.[ref]
Let’s take a look at some of the recent studies:
Higher PCSK9 levels in people with cancer:
A study published in 2022 found that PCSK9 levels were significantly higher (95.9 ng/mL) in women with breast cancer (stage III) compared to a matched control group of women with benign breast lesions (78.5 ng/mL). Note that the LDL and HDL cholesterol levels were the same for the control group and the stage III cancer group – only PCSK9 was different. [ref]
Pancreatic cancer: Longer survival with lower PCSK9
Low serum PCSK9 levels correlate to a longer overall survival time in pancreatic cancer patients (more than twice as long). In this study from Sept. 2024, higher PCSK9 was linked to cancerous cells invading the lymph nodes (metastasis).[ref]
Gastric cancer: Higher PCSK9 promotes metastasis
In gastric cancer, higher PCSK9 levels promoted cancer cell migratory ability (metastasis). The study also found that gastric cancer patients had higher serum levels of PCSK9 than an age-matched healthy control group.[ref]
Lung cancer: Slightly lower recurrence with lower PCSK9
A retrospective study of non-small cell lung cancer patients showed that patients with low PCSK9 had a recurrence rate of 42%, while patients with high PCSK9 had a recurrence rate of 58%. When looking at overall survival, high PCSK9 increased the relative risk of death by 64%.[ref]
Animal studies demonstrating the mechanism:
In mice, tumors deficient in PCSK9 grow more slowly or are prevented from growing at all – but only in certain strains of laboratory mice. In other strains of laboratory mice, PCSK9 deficiency had no effect on tumor growth.[ref]
Other studies in animal cell lines show that inhibiting PCSK9 allows for an increase in cancer-fighting T cells. Importantly, the combination of checkpoint inhibitor therapy plus PCSK9 inhibition helped make checkpoint inhibitor therapy much more effective.[ref]
Additionally, a mouse study showed that inhibiting PCSK9 with a novel inhibitor suppressed breast tumor recurrence. The PCSK9 inhibitor not only decreased plasma cholesterol levels but also 17β-estradiol levels.[ref]
In melanoma, animal studies also show that higher PCSK9 levels increase the risk of metastasis and contribute to immune evasion.[ref]
Genetics, PCSK9, and Cancer Recurrence:
Genetic variants in PCSK9 were identified in 2003 as playing a role in LDL cholesterol levels. The gain-of-function PCSK9 variants that significantly increase LDL cholesterol are associated with an increased risk of cardiovascular disease. This discovery led to the creation of PCSK9 inhibitor drugs that are now available as an alternative to stations for lowering cholesterol levels.
Researchers also discovered that loss-of-function PCSK9 variants caused lower cholesterol levels — and a decreased risk of heart disease.
Breast Cancer Recurrence Linked to a PCSK9 Variant:
A new study shows that PCSK9 genetic variants also impact the recurrence risk for breast cancer. The study looked at a large cohort of women with breast cancer and their recurrence rate and survival. The results showed that a common variant with higher PCSK9 levels was linked to higher rates of cancer recurrence and metastasis (22%), while the women with the lower PCSK9 variant had a lower rate of recurrence with metastasis (2%). Using a mouse model of breast cancer, the research found that the LDL receptor wasn’t involved in the increased cancer metastasis. Instead, they pinpointed the LRP1 receptor as the key. The research also showed that LRP1 interacted with a set of interferon-related genes (XAF1, OAS1A, ISG15, USP18, and RTP4) that were also upregulated in women with breast cancer and higher PCSK9 expression. Depletion of XAF1, specifically, was shown to decrease metastasis. This gene set has been shown in other studies, as well, to increase the risk of recurrence and metastasis.[ref]
Note: The study was funded by a pharma company that develops cancer therapies with a potential financial interest in PCSK9 inhibitors as a cancer therapy. This doesn’t mean that the study isn’t valid – it seems to be very thorough – but it is something to note. Hopefully, more studies on the topic will be in the works.
Let’s take a look now at your PCSK9 genetic variants, and then we will go into ways to naturally decrease PCSK9 in the Lifehacks section.
Genotype report: PCSK9
Lifehacks:
If you have had cancer, talk with your oncologist or primary care doctor about whether inhibiting PCSK9 would be beneficial in preventing metastatic recurrence for your specific type of cancer. Prescription PCSK9 inhibitors are available to lower cholesterol. Note that the long-term studies of PCSK9 inhibitors all show that they reduce the risk of cardiovascular disease. Keep in mind that there are always tradeoffs — higher PCSK9 may be beneficial for fighting off certain pathogens as well as for preventing diabetes, and PCSK9 inhibitors may also increase connective tissue disorders.[ref][ref][ref] So talk with your doctor about the pros and cons here.
If you have higher cholesterol levels and think that targeting PCSK9 would be helpful for preventing heart disease, below are some of the research studies on natural ways to inhibit PCSK9.
Lifestyle and diet:
Weight loss:
Obesity upregulates PCSK9 levels, and losing weight may help to decrease PCSK9 if you are overweight. A study in overweight teenagers showed that a low-calorie diet reduced PCSK9 levels.[ref][ref]
Increased omega-3:
Studies show that plasma PCSK9 levels are lower with higher concentrations of omega-3 polyunsaturated fatty acids.[ref] Good sources of omega-3 fatty acids include fatty fish, pasture-raised eggs, and marine oil supplements.
Intermittent fasting or time-restricted eating:
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