Abstract
The p53 gene is an important tumour suppressor gene. Mutant p53 genes account for about half of all lung cancer cases. There is increasing evidence for the anti-tumour effects of statins via inhibition of the mevalonate pathway. We retrospectively investigated the correlation between statin use and lung cancer prognosis using the Taiwanese National Health Insurance Research Database, mainly focusing on early-stage lung cancer. This study reports the protective effects of statin use in early-stage lung cancer patients regardless of chemotherapy. Statin treatments reduced the 5-year mortality (odds ratio, 0.43; P < 0.001) in this population-based study. Significantly higher levels of cellular apoptosis, inhibited cell growth, and regulated lipid raft content were observed in mutant p53 lung cancer cells treated with simvastatin. Further, simvastatin increased the caspase-dependent apoptotic pathway, promotes mutant p53 protein degradation, and decreased motile activity in lung cancer cells with p53 missense mutations. These data suggest that statin use in selected lung cancer patients may have clinical benefits.
Highlights
Statins, which target the rate-limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase), are used as lipid-lowering agents to reduce cardiovascular events in patients at risk for atherosclerotic vascular disease[1]
We found that simvastatin is more toxic in lung adenocarcinomas that harbour TP53 mutations, providing a possible therapeutic strategy in lung cancer treatment
To investigate whether decreased cell survival associated with simvastatin treatment is accompanied by apoptotic features, we examined the distribution of apoptotic cells using annexin-V/propidium iodide (PI) staining in cell lines with a different p53 status, including null (H1299), wild type (A549), mutant p53 (Bm7-shGFP, HCC827-shGFP), and knock-down (Bm7-shTP53, HCC827-shTP53) cells
Summary
Statins, which target the rate-limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase), are used as lipid-lowering agents to reduce cardiovascular events in patients at risk for atherosclerotic vascular disease[1]. They reduce long-term coronary heart disease events and related mortalities in patients without risk of cardiovascular disease[2]. In recent population-based studies, long-term statin use reduced overall lung cancer mortality[7,8]. A population-based cohort study revealed that lipophilic simvastatin is more efficacious at reducing rates of cancer-specific mortality than other hydrophilic statins[9]. We found that simvastatin is more toxic in lung adenocarcinomas that harbour TP53 mutations, providing a possible therapeutic strategy in lung cancer treatment
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