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Published on: July 21, 2018
MCM2 is a therapeutic target of lovastatin in human non-small cell lung carcinomas
Xu Zhang1, Yang Teng2, Fang Yang3
1Department of Stomatology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China.
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.
Insights
Lovastatin inhibits non-small cell lung cancer (NSCLC) proliferation by downregulating minichromosome maintenance 2 (MCM2) expression. This study identifies MCM2 as a potential therapeutic target for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Human non-small cell lung carcinoma (NSCLC) is a prevalent global cancer.
- Lovastatin, a 3-hydroxy-3-methylglutaryl Co A (HMG-CoA) reductase inhibitor, shows antitumor potential.
- The role of minichromosome maintenance 2 (MCM2) in lovastatin's anti-NSCLC effects is not fully understood.
Purpose of the Study:
- To investigate if lovastatin inhibits NSCLC proliferation by affecting MCM2 expression.
- To elucidate the molecular mechanisms underlying lovastatin's action on NSCLC cells, focusing on MCM2.
Main Methods:
- Quantitative RT-PCR and western blot analysis to assess MCM2 expression.
- Small interfering RNA (siRNA) to silence MCM2 in NSCLC cell lines (A549, GLC-82).
- Cell cycle analysis, apoptosis assays, and examination of cell cycle-related proteins (Rb, cyclin D1, CDK4, p21, p53, p-JNK).
Main Results:
- Lovastatin treatment significantly inhibited MCM2 expression in NSCLC cells.
- MCM2 silencing (siMCM2) induced G1/S phase arrest and apoptosis.
- MCM2 knockdown altered the expression of cell cycle regulators, including decreased Rb, cyclin D1, CDK4 and increased p21, p53.
- Lovastatin treatment increased phosphorylated c-Jun N-terminal kinase (p-JNK), linked to MCM2 downregulation.
Conclusions:
- MCM2 plays a crucial role in NSCLC proliferation and survival.
- Lovastatin exerts anti-NSCLC effects, at least partly, through the inhibition of MCM2 expression.
- MCM2 represents a promising novel therapeutic target for lovastatin-based NSCLC treatment.
