Abstract
Cancer is, fundamentally, a disorder of cell growth and proliferation, which requires adequate supplies of energy and nutrients. In this study, we report that the haplo-insufficient tumor suppressor ASPP2, a p53 activator, negatively regulates the mevalonate pathway to mediate its inhibitory effect on tumor growth in hepatocellular carcinoma (HCC). Gene expression profile analysis revealed that the expression of key enzymes in the mevalonate pathway were increased when ASPP2 was downregulated. HCC cells gained higher cholesterol levels and enhanced tumor-initiating capability in response to the depletion of ASPP2. Simvastatin, a mevalonate pathway inhibitor, efficiently abrogated ASPP2 depletion-induced anchorage-independent cell proliferation, resistance to chemotherapy drugs in vitro, and tumor growth in xenografted nude mice. Mechanistically, ASPP2 interacts with SREBP-2 in the nucleus and restricts the transcriptional activity of SREBP-2 on its target genes, which include key enzymes involved in the mevalonate pathway. Moreover, clinical data revealed better prognosis in patients with high levels of ASPP2 and low levels of the mevalonate pathway enzyme HMGCR. Our findings provide functional and mechanistic insights into the critical role of ASPP2 in the regulation of the mevalonate pathway and the importance of this pathway in tumor initiation and tumor growth, which may provide a new therapeutic opportunity for HCC.
Highlights
Dysregulation of a wide range of metabolic pathways can be involved in carcinogenesis[1]
To explore the mechanisms driving the inhibitory effects of ASPP2 on tumor growth and progression, we performed a microarray analysis to identify the potential down-stream targets of ASPP2 by comparing gene expression in ASPP2-depleted hepatocellular carcinoma (HCC)-LM3 cells and parent cells
The results revealed that the mRNA and protein levels of hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and HMGCS1 were notably elevated in ASPP2-depleted HCC-LM3 and HepG2 cells (Figs. 1c and d)
Summary
Dysregulation of a wide range of metabolic pathways can be involved in carcinogenesis[1]. Cholesterol has a critical role in maintaining the stability and architecture of the plasma membrane and is needed by highly proliferative cancer cells[2]. Tumor cell membranes have been found to be enriched in cholesterol, suggesting that enhanced cholesterol utilization is an important feature of malignant and perhaps metastatic tumors[3]. Clinical and experimental findings suggest that malignant cells and tissues need higher amounts of cholesterol and intermediates of the mevalonate pathway than their normal counterparts[5,6]. Some types of cancers, such as hepatocellular carcinoma (HCC), depend on mevalonate pathway for growth. Inhibition of mevalonate metabolism suppresses tumor initiation and growth in a myc-transgenic murine HCC model[7], activation of the mevalonate pathway plays an essential role in liver tumorigenesis caused by p53 loss in mice[8]
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