Cholesterol’s Role in Cancer Development
Cholesterol, an amphiphilic sterol molecule, plays a crucial role in maintaining cell membrane integrity by regulating its fluidity, ion channels, and protein organization. Cellular cholesterol homeostasis is preserved through a balance of de novo synthesis, uptake, efflux, and esterification.
Research has shown that cholesterol metabolism influences tumor growth by facilitating membrane biogenesis and signal transduction. Disruptions in cholesterol homeostasis have been linked to cancer progression. For instance, elevated levels of ATP-binding cassette transporter A1 (ABCA1) promote cholesterol efflux, increasing membrane fluidity, which in turn enhances the metastatic potential of triple-negative breast cancer (TNBC).
Various therapeutic approaches targeting cholesterol metabolism—such as enzyme inhibitors and transport protein modulators—have been explored for their anti-cancer properties. However, these treatments often suffer from limited long-term efficacy, adverse side effects, and drug resistance.
To address these challenges, researchers are investigating novel therapeutic options, including Traditional Chinese Medicine (TCM). TCM-based natural compounds have shown promise in regulating cholesterol metabolism for cancer treatment. A recent study highlighted that quercetin, a bioactive compound found in TCM, can reduce cholesterol synthesis by activating adenosine monophosphate-activated protein kinase (AMPK) and inhibiting 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR).
Targeting Cholesterol Biosynthesis
Most cells, except mature red blood cells and brain tissue, have the capability to synthesize cholesterol through an ATP-intensive process involving nearly 30 enzymatic reactions and over 15 proteins. Genetic mutations or disruptions in enzymes related to cholesterol homeostasis can drive cancer progression.
Key regulators of cholesterol biosynthesis include sterol regulatory element-binding protein 2 (SREBP2), HMGCR, and squalene epoxidase (SQLE). These molecules serve as potential therapeutic targets for natural compounds.
For example, artesunate (ART), an artemisinin derivative, inhibits cholesterol synthesis by targeting SREBP2. Additionally, gypenoside L, a natural compound, modulates the mevalonate (MVA) pathway by influencing SREBP2, which is crucial for hepatic tumor stem cell growth.
Other plant-derived compounds such as emodin (from Reynoutria japonica) and osthole (from Cnidium monnieri) work synergistically to suppress SREBP2 activity through pathways involving nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt. However, further research is needed to fully understand their mechanism of action.
Another promising compound, alpineisoflavone (AIF), exhibits anti-cancer properties by inhibiting androgen receptor (AR) expression, thereby disrupting HMGCR-mediated cholesterol biosynthesis.
Cholesterol Uptake as a Target for Cancer Therapy
Rapidly growing cancer cells depend on external cholesterol sources, utilizing transport proteins such as niemann-pick type C1-like 1 (NPC1L1) and low-density lipoprotein receptor (LDLR) to facilitate cholesterol uptake. Though ezetimibe, a widely used NPC1L1 inhibitor, is effective in treating hypercholesterolemia, its anti-cancer effects remain limited.
Natural compounds such as curcumin, derived from turmeric, have demonstrated potential in reducing lung, breast, and colorectal cancers by promoting intracellular cholesterol transport through transient receptor potential A1 (TRPA1) activation. Curcumin has also been shown to decrease SREBP2 and NPC1L1 levels in a dose-dependent manner.
Another promising bioactive compound, isoglycyrrhizin, extracted from Glycyrrhiza uralensis, inhibits cholesterol uptake by downregulating NPC1L1 expression without significant cytotoxic effects. Meanwhile, chrysanthemone, a compound derived from Tanacetum parthenium, is a potent NPC1L1 inhibitor, though its anti-cancer properties remain to be explored.
Enhancing Cholesterol Efflux for Cancer Treatment
Studies indicate that the ATP-binding cassette (ABC) transporter family and liver X receptor (LXR) play key roles in cholesterol efflux. Certain small molecules have been found to enhance these pathways, leading to anti-cancer effects.
Celastrol, a triterpenoid extracted from Tripterygium wilfordii, has demonstrated potent anti-cancer activity by suppressing clear cell renal carcinoma (ccRC) tumor growth in a dose-dependent manner. Celastrol increases ABCA1 expression in tumor tissues, promoting cholesterol efflux, lipid metabolism, and reducing cholesterol accumulation in cancer cells.
Targeting Cholesterol Esterification to Combat Cancer
Cholesterol can be converted into cholesteryl esters (CEs) by acyl-coenzyme A: cholesterol acyltransferase (ACAT). The accumulation of CEs is critical for tumor cells, as it provides cholesterol necessary for maintaining membrane stability and function. CE accumulation has also been associated with the loss of tumor-suppressor gene phosphatase and tensin homolog (PTEN).
Manzamine A, a bioactive compound, has shown promise in inhibiting cholesterol esterification by targeting ACAT2, thereby exerting anti-cancer effects. Recent murine melanoma studies have also demonstrated that avasimibe, an ACAT inhibitor, effectively reduces CE levels, supporting its potential role in cancer therapy.
