| Summary: | 博士 === 國立臺灣大學 === 藥理學研究所 === 97 === The novel anticancer mechanisms of thalidomide and HMG-CoA reductase inhibitors (statins) were investigated in this study. Thalidomide has been reported to have anti-angiogenic and anti-metastatic effects. Intercellular adhesion molecule-1 (ICAM-1) was demonstrated to be involved in cancer cell invasion. We investigated the role of ICAM-1 in tumorigenesis. High expression of ICAM-1 in human lung cancer specimens was correlated with a greater risk of advanced cancers (stage III and IV). A549/ICAM-1 cells were demonstrated to induce in vitro cell invasion and in vivo tumor metastasis. Anti-ICAM-1 antibody and thalidomide had inhibitory effect on these events. Thalidomide also suppressed tumor nacrosis factor-alpha(TNF-alpha-induced ICAM-1 expression through inhibition of nuclear factor-kappaB (NF-kappaB) binding to the ICAM-1 promoter. The in vivo xenograft model showed the effectiveness of thalidomide on tumor formation.
We show that statins inhibited histone deacetylase (HDAC) activity, increased the accumulation of acetylated histone-H3 and the expression of p21 in human cancer cells. Computational modeling demonstrated the direct interaction of the carboxylic acid moiety of statins with the catalytic site of HDAC2. Transcription factor Sp1 but not p53 sites was found to be the statins-responsive element demonstrated by p21 luciferase-promoter assays. DNA-affinity protein binding assay (DAPA) and chromatin immunoprecipitation assay (ChIP) assays showed the dissociation of HDAC1/2 and association of CREB-binding protein (CBP), leading to the histone-H3 acetylation on the Sp1 sites of p21 promoter.
Autophagy is a process describing the degradation and recycling of proteins or intracellular organelles. In this study, we found that statins induced autophagy through a mechanism relying on AMP-activated protein kinase (AMPK) activation. Statins activate AMPK, leading to inhibition of mTOR and expression of p21. AMPK inhibitor and AMPK siRNA abrogated atorvastatin-induced autophagy, which was also attenuated in p21-/- HCT116 cells. Positive correlation between the reduced expression of p21 and beclin 1 was seen in human colon cancer specimens. Overexpression of p21 induced not only LC3-II expression but also phosphorylation of eIF2alpha suggesting that p21 induces autophagy through ER stress signaling. Taken together, all the results provide a mechanistic insight into the crucial role of thalidomide and statins in anti-cancer therapy.
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