Abstract
Convincing evidence indicates that statins stimulate apoptotic cell death in several types of proliferating tumor cells in a cholesterol-lowering-independent manner. However, the relationship between apoptosis and autophagy in lymphoma cells exposed to statins remains unclear. The objective of this study was to elucidate the potential involvement of autophagy in fluvastatin-induced cell death of lymphoma cells. We found that fluvastatin treatment enhanced the activation of pro-apoptotic members such as caspase-3 and Bax, but suppressed the activation of anti-apoptotic molecule Bcl-2 in lymphoma cells including A20 and EL4 cells. The process was accompanied by increases in numbers of annexin V alone or annexin V/PI double positive cells. Furthermore, both autophagosomes and increases in levels of LC3-II were also observed in fluvastatin-treated lymphoma cells. However, apoptosis in fluvastatin-treated lymphoma cells could be blocked by the addition of 3-methyladenine (3-MA), the specific inhibitor of autophagy. Fluvastatin-induced activation of caspase-3, DNA fragmentation, and activation of LC3-II were blocked by metabolic products of the HMG-CoA reductase reaction, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These results suggest that autophagy contributes to fluvastatin-induced apoptosis in lymphoma cells, and that these regulating processes require inhibition of metabolic products of the HMG-CoA reductase reaction including mevalonate, FPP and GGPP.
Highlights
Malignant lymphoma (ML), a heterogeneous disease with highly variable clinical course and prognosis, is the most common type of adult leukemia [1]
Our results showed that the numbers of apoptotic cells (AV-FITC alone positive and Annexin V (AV)/Propidium iodide (PI) double positive cells) in both A20 and EL4 cells treated with fluvastatin were greatly increased in a dose-dependent manner (Figure 1A and C)
Effects of fluvastatin on activation of apoptosis-related molecules To further explore the molecular mechanism by which fluvastatin induces apoptosis in lymphoma cells, the activation of several apoptosis relevant molecules was assessed by Western blotting
Summary
Malignant lymphoma (ML), a heterogeneous disease with highly variable clinical course and prognosis, is the most common type of adult leukemia [1]. Most patients with malignant lymphomas in clinical course are aggressive and soon after diagnosis require intensive treatment [2]. Both the defective balance between pro- and anti-apoptotic molecules and aberrant up-regulation of pro-survival signals had been shown to be related to resistance of malignant lymphoma cells to radiation therapy and chemotherapy [3]. The inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, are used to treat hypercholesterolemia Convincing evidence from both in vitro and in vivo data has demonstrated that statins exert pleiotropic actions beyond their lipid-lowering effects, including immune regulation [4] and cancer prevention [5,6]. Statins have been demonstrated to induce cell cycle arrest and cell death in various cancer cells such as multiple myeloma cells [7], pancreatic cancer cells [8], non-small lung cancer cells [9], waldenstrom macroglobulinemia cells [10], and breast cancer MCF-7 cells [11]
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