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Dihydroartemisinin induces cell apoptosis through repression of UHRF1 in prostate cancer cells
1Laboratory of Medical Experiment Technology, Institute of Life Science, Chongqing Medical University, Chongqing, China.
Abstract:
Prostate cancer (PCa) seriously jeopardizes men's health worldwide. Dihydroartemisinin, which is an effective antimalarial agent, has shown potential anticancer effects in various human cancer cell lines, including PCa cells. However, the mechanisms underlying the anticancer activity of dihydroartemisinin are not fully understood. Ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1) is highly expressed in a variety of tumors and is negatively correlated with the prognosis of various tumors. We reported previously that UHRF1 is downregulated during apoptosis induced by dihydroartemisinin in PC-3 PCa cells. In this study, we transfected PC-3 cells with lentiviruses containing UHRF1 or shRNA-UHRF1. Then, the cells were treated with dihydroartemisinin at different concentrations. Our data showed that overexpression of UHRF1 promoted cell proliferation and migration in PC-3 cells, inhibited cell apoptosis, increased cell proportion in G2 phase, increased DNA methyltransferase 1 and decreased p16INK4A expression at mRNA and protein levels. Downregulation of UHRF1 produces the opposite results. Moreover, the phenomena caused by overexpression of UHRF1 were inhibited after dihydroartemisinin treatment. Compared with control cells, cells overexpressing UHRF1 can resist the proapoptotic and antiproliferative effects of dihydroartemisinin to a certain extent. The effects of UHRF1 knockdown were further aggravated by dihydroartemisinin treatment, but no statistically significant effect was observed with increasing drug concentration. Our results suggested that dihydroartemisinin decreases proliferation and migration but enhances apoptosis of PCa cells, likely by downregulating UHRF1 and upregulating p16INK4A.
Insights
Dihydroartemisinin combats prostate cancer by reducing cell growth and migration while promoting cell death. This effect is linked to decreased expression of UHRF1 (Ubiquitin-like with plant homeodomain and ring finger domain 1) and increased p16INK4A.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer (PCa) is a significant global health concern for men.
- Dihydroartemisinin, an antimalarial drug, exhibits potential anticancer properties.
- The precise mechanisms of dihydroartemisinin's anticancer activity, particularly in PCa, require further elucidation.
Purpose of the Study:
- To investigate the role of Ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1) in the anticancer effects of dihydroartemisinin on PCa cells.
- To explore how UHRF1 expression influences PCa cell proliferation, apoptosis, and migration in response to dihydroartemisinin treatment.
Main Methods:
- PC-3 PCa cells were transfected to overexpress or downregulate UHRF1.
- Cells were subsequently treated with varying concentrations of dihydroartemisinin.
- Cell proliferation, apoptosis, cell cycle, and expression of DNA methyltransferase 1 and p16INK4A were assessed at mRNA and protein levels.
Main Results:
- Overexpression of UHRF1 enhanced PC-3 cell proliferation and migration, inhibited apoptosis, and altered cell cycle distribution.
- UHRF1 downregulation yielded opposite effects.
- Dihydroartemisinin treatment counteracted the pro-proliferative and anti-apoptotic effects of UHRF1 overexpression, while enhancing the effects of UHRF1 knockdown.
Conclusions:
- Dihydroartemisinin exerts antiproliferative and pro-apoptotic effects on PCa cells, potentially through the downregulation of UHRF1 and upregulation of p16INK4A.
- UHRF1 plays a critical role in modulating the sensitivity of PCa cells to dihydroartemisinin.
- Targeting UHRF1 may represent a therapeutic strategy in prostate cancer treatment.
