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Cell killing and radiosensitizing effects of atorvastatin in PC3 prostate cancer cells
Zhenhua He1, Lingegowda S Mangala, Corey A Theriot
1University of Houston at Clear Lake, Houston, Texas 77058, USA.
Abstract:
Recent studies have indicated that autophagy may be one of the important pathways induced by ionizing radiation. Atorvastatin (statin), an inhibitor of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, may exhibit anticancer effects as an autophagy inducer. In our study, the cell killing and radiosensitizing effects of statin were analyzed in PC3 cell line. Activation of the autophagy pathway was analyzed using the GFP-LC3 assay and western blot to determine LC3-II expression. The radiosensitivity of PC3 cells was determined using the clonal survival assay, TUNEL assay, and the Annexin V apoptosis assay. The expression profiles of autophagy related genes were analyzed using a pathway specific real-time polymerase chain reaction (PCR) array. Autophagic response was induced in PC3 cells after exposure to statin and/or gamma rays. Inhibition of the autophagic process using small interfering RNAs (siRNA) targeting Atg7 and/or Atg12 significantly reduced radiosensitivity of PC3 cells. Statin also exhibited a significant apoptosis-inducing effect in PC3 cells, which can be partially suppressed by Atg7 siRNA. Cells treated with statin and gamma irradiation showed significantly reduced colony forming efficiency and increased number of Annexin V positive early apoptotic cells. Analysis of autophagy and its regulatory gene profile showed that the expressions of 22 genes out of 86 genes assessed were significantly altered in the cells exposed to combined treatment or statin alone. The data indicate that activation of the autophagy pathway may be responsible for apoptosis inducing effect of statin. Furthermore, combined treatment with radiation and autophagic inducer, such as statin, may be synergistic in inducing cell death of PC3 cells.
Insights
Atorvastatin (statin) enhances cancer cell killing by inducing autophagy, a cellular process. Combining statin with radiation therapy shows synergistic effects, increasing cancer cell death and apoptosis in PC3 cells.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Autophagy is implicated in cellular responses to ionizing radiation.
- Atorvastatin (statin), a HMG-CoA reductase inhibitor, may act as an autophagy inducer with anticancer potential.
Purpose of the Study:
- To investigate the cell-killing and radiosensitizing effects of atorvastatin in PC3 cancer cells.
- To determine the role of autophagy in atorvastatin-induced radiosensitization and apoptosis.
Main Methods:
- Analysis of autophagy activation using GFP-LC3 assay and Western blot for LC3-II expression.
- Assessment of radiosensitivity via clonal survival, TUNEL, and Annexin V assays.
- Gene expression profiling of autophagy-related genes using real-time PCR array.
Main Results:
- Atorvastatin and gamma irradiation induced autophagy in PC3 cells.
- Inhibition of autophagy (Atg7/Atg12 siRNA) reduced radiosensitivity.
- Combined treatment significantly decreased colony formation and increased early apoptosis.
- Expression of 22 out of 86 autophagy-related genes was significantly altered.
Conclusions:
- Autophagy activation by atorvastatin contributes to its apoptosis-inducing effects.
- Combined atorvastatin and radiation therapy demonstrates synergistic cancer cell death in PC3 cells.
