MCM2 is a therapeutic target of lovastatin in human non-small cell lung carcinomas

Abstract

Human non-small cell lung carcinoma (NSCLC) is one of the most common cancer worldwide. In previous studies, lovastatin, acting as an inhibitor of 3-hydroxy-3-methylglutaryl Co A (HMG-CoA) reductase, exhibited significant antitumor activity during tumorigenesis. However, whether or not this effect is mediated through changes in minichromosome maintenance (MCM) 2 expression remains unclear. The present study investigated whether lovastatin inhibits proliferation due to MCM2 in NSCLCs. We first assessed the effects of lovastatin on cell anti-proliferation, cell cycle progression and apoptosis in NSCLC cells. We found, by quantitative RT-PCR and western blot analysis, that lovastatin treatment markedly and consistently inhibited the expression of MCM2. Then, to further explore the anticancer mechanism of lovastatin involving MCM2, we silenced MCM2 by siRNA in two cell lines (A549 and GLC-82). Silencing of MCM2 triggered G1/S arrest. Following further examination of cell cycle-related factors, MCM2 knockdown inhibited protein retinoblastoma (Rb), cyclin D1 and CDK4 expression, but increased p21 and p53 expression, suggesting that siMCM2 indeed triggered cell cycle arrest. In addition, siMCM2 induced apoptosis. Finally, lovastatin treatment increased p-JNK, which is involved in the downregulation of MCM2. In conclusion, our data suggest that MCM2 may be a novel therapeutic target of lovastatin treatment in NSCLCs.

Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1

“…Lovastatin-treated animals showed significantly reduced MACC1 mRNA expression ( p < 0.05), confirming that the drug acts as a transcriptional inhibitor of MACC1 and thus inhibits MACC1-induced metastasis formation in vivo. In order to analyze further drug-induced effects, we determined the mRNA expression of genes that can be regulated by lovastatin (DNMT1, Col1A1, and MCM2) [34–36]. DNMT1 and MCM2 showed no significant expression regulation upon treatment with lovastatin, whereas Col1A1 was significantly down-regulated, and HMGCR was significantly up-regulated (S3 Fig).…”

MCMs in Cancer: Prognostic Potential and Mechanisms

“…Many studies have provided cytological evidence for bioinformatics analysis that MCMs are involved in the progression of cell cycle pathways ( Figure 2). Knockdown of MCM2 reduced Rb, cyclinD1, cyclinA, and CDK4 expression and increased p53 and p21 expression, suggesting that by inducting the Cdk inhibitor p21cip14 and cyclin D/CDK4, downregulated MCM2 triggered the arrest of G1/S or G2/M [50,62]. Knockdown of MCM3 caused G1 arrest as evidenced by reduced expression of cyclinA [50].…”

“…The first strategy is to target MCM genes at transcriptional levels. It was shown that Trichostatin A, an HDAC inhibitor, and Lovastatin, an HMG-CoA reductase inhibitor, could downregulate MCM2 through activation of the JNK signaling pathway [60][61][62]. Also, Widdrol, an odorant compound, can activate DNA damage checkpoint through the signaling Chk2-p53-Cdc25A-p21-MCM4 pathway in HT29 cells [63].…”

Integrative module analysis of HCC gene expression landscapes

“…In addition, CCNB2 is key protein of the cyclin family and regulates the progression of the G2/M transition during the cell cycle (46). Furthermore, CCNB2, MAD2L1 and MCM2 are mitotic checkpoint associated proteins that are overexpressed in numerous types of human cancer (47)(48)(49). The dysregulation of mitotic checkpoints may also result in aneuploidy and the promotion of tumorigenesis (50).…”