The mechanistic insights behind the anticancer effects of statins in liver cancer

Statins are a class of drugs widely used clinically for the management of high cholesterol and the prevention of cardiovascular diseases. Currently, 7 statins are available on the market, including lovastatin, simvastatin, atorvastatin, fluvastatin, pravastatin, rosuvastatin, and pitavastatin. Statins function as the competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) by occupying enzyme binding pocket at the nanomolar levels. HMGCR is the enzyme responsible for converting HMG-CoA to mevalonate (MVA), acting as the pivotal gatekeeper in the MVA pathway, which plays a crucial role in cholesterol biosynthesis. The MVA pathway begins with the substrate acetyl-CoA and goes through a series of enzymatic reactions to generate isopentenyl pyrophosphate. Isopentenyl pyrophosphate then undergoes condensation reactions to produce various macromolecules, including cholesterol, steroid products, dolichol, and coenzyme Q10. These metabolites are essential for many critical cellular functions. The metabolic intermediates from the MVA pathway play vital roles in promoting cancer growth. Two MVA metabolites, geranylgeranyl pyrophosphate and farnesyl pyrophosphate, facilitate protein prenylation, a posttranslational modification necessary for the membrane localization and hence activating the Rho GTPases and Ras GTPases. In addition, coenzyme Q10 functions as a lipophilic antioxidant that alleviates oxidative stress. ¹ Cancer cells have increased metabolic demand for MVA-derived products. Given HMGCR’s essential roles in the MVA pathway, statins might have potential as anticancer drugs.

HCC remains a global health challenge with no curative treatment. Growing evidence demonstrated the shift of HCC etiology from virus-mediated HCC to non–virus-related HCC, accompanied by liver metabolic disorders. ² Statins, as the anticholesterol biosynthesis agents, were evaluated for their potential in preventing HCC in epidemiological studies. It has been reported that statin users have a lower risk for HCC and liver-related mortality. ³ An observational clinical study found that patients with metabolic dysfunction–associated steatotic liver disease who had cumulative statin exposure greater than 600 defined daily doses exhibited a 70% decrease in the risk of HCC development. ⁴ Remarkably, several population-based cohort studies consistently demonstrated the preventive effects of statins in HBV/HCV-associated HCC. ^5,6 Statins were shown to be associated with a reduced hazard of liver cancer or liver-related mortality in a cohort of patients with chronic HBV and dyslipidemia. ⁶ Higher dosage of statins was linked to progressively lower risks of decompensation, mortality, and HCC in individuals with hepatitis virus-related cirrhosis. ⁷ In addition, recent reports showed that statins also reduced HCC incidence and mortality in patients with alcohol-associated liver disease. ⁸ Statins were also associated with decreased tumor recurrence and a more favorable prognosis in patients who received surgical treatments such as hepatectomy or liver transplantation. ^9,10 In line with the above clinical studies, mechanistic studies further demonstrated the anticancer effects of statins in the context of HCC. Specifically, atorvastatin disrupted lipogenesis and reversed the metabolically dysregulated gut microbiota caused by a high-fat/high-cholesterol diet regimen in HCC. ¹¹ Moreover, statins were shown to influence the pathogenicity of hepatitis viruses. Statins reversed HBV-induced Akt phosphorylation and inhibited cholesterol ester synthesis, large lipid droplet formation, and HCV viral secretion within the hepatocytes. ^12,13 Overall, a mounting body of clinical and preclinical evidence has revealed the beneficial impact of statins in patients who are at risk of liver cancer due to various underlying etiological factors.

CAN STATINS TREAT LIVER CANCER IN ADDITION TO THEIR PREVENTIVE EFFECTS?

Recent studies have uncovered statins’ various metabolic modulatory roles, such as suppressing cholesterol and different MVA metabolites, enabling statins to synergize with other FDA-approved drugs in suppressing HCC. Classically, statins restrained the dysregulated cholesterol and improved the clinical outcomes of HCC. Liver cancer activated cholesterol biosynthesis through multiple signaling pathways such as MEK/ERK and c-Fos/LXRα, which supported cancer cell proliferation and protected liver tumors from apoptosis. ¹⁴ Statins treatment repressed MEK/ERK-mediated cholesterol production to inhibit HCC proliferation, metastasis, and TGF-β1/pERK-mediated angiogenesis. ^15,16 Besides, the MVA pathway is essential for the function of the small GTPase protein Rho due to the posttranslational modification mediated by geranylgeranyl pyrophosphate. Statins restrained HCC growth by inhibiting Rho, which otherwise activated YAP/TAZ, the oncogenic effectors of the Hippo pathway. ^17,18 Moreover, activation of the MVA pathway promoted the chemoresistance in HCC by inducing cholesterol accumulation. ¹⁹ Statins reversed the YAP-mediated chemoresistance in HCC and amplified the cytotoxic properties when combined with EGFR signaling inhibitor, chemotherapeutics dasatinib, and autophagic inhibitor. ^20–22 Excitingly, statins elicited the most potent cytotoxicity effect when combined with tyrosine kinase inhibitors. ²³ Besides, elevating cholesterol production promoted the TAZ/TEAD2-mediated PD-L1 expression in HCC tumors. The use of statins worked synergistically with immune checkpoint inhibitors such as anti-PD1 and anti-PDL1 to suppress HCC tumors. ¹⁷ In addition, statins remodeled the tumor microenvironment by reducing the IL-6 secretion to suppress the infiltration of tumor-associated macrophages and inducing CXCL6 to recruit cytotoxic natural killer T cells, thereby enhancing the efficiency of immune checkpoint inhibitor treatment. ^24,25

In conclusion, statins are the key inhibitors of the MVA pathway, and they not only reduce lipid levels but also suppress the production of MVA metabolites, thereby impeding the initiation and development of HCC (Fig. 1). By targeting this central metabolic pathway, statin-based therapies can potentially disrupt multiple steps involved in HCC progression. Recent clinical studies have revealed the potential of statins in preventing HCC, prompting more translational studies to test their effectiveness as single agent or in combination with other HCC drugs in various preclinical models. In addition, further mechanistic studies are warranted to fully elucidate the complex roles of the MVA pathway in HCC pathogenesis and to explore more MVA inhibitors for HCC treatment.

FIGURE 1.

The mechanisms by which statins suppress the growth of liver cancer cells through targeting the mevalonate pathway. (Figure is generated by Biorender).

FUNDING INFORMATION

This study is supported by National Natural Science Foundation of China—the Excellent Young Scientist Fund (Hong Kong and Macau) (Project#82022077), Research Grant Council Collaborative Research Fund (RGC CRF) (C7008-22G) (C5106-23G), Health and Medical Research Fund (HMRF) (10212546), Research Grant Council Research Impact Fund (RGC RIF) (R5008-22), Research Grant Council Theme Based Research Scheme (RGC TBRS) (T12-716/22-R), and Shenzhen Science and Technology Program (ZDSYS20210623091811035). This work is supported by the Centre for Oncology and Immunology under the Health@InnoHK initiative funded by the Innovation and Technology Commission, the Government of Hong Kong SAR, China. Carmen Chak-Lui Wong is the recipient of the University of Hong Kong Outstanding Research Supervisor Award.

CONFLICTS OF INTEREST

The authors have no conflicts to report.