cyclin-d1 and celastrol

Human estrogen receptor α (ERα) is a nuclear transcription factor that displays a major therapeutic target for breast cancer. The transcriptional activity of ERα can be regulated by particular estrogen receptor modulators. Celastrol, a quinine methide triterpene extracted from a Chinese medicine (Trypterygium wilfordii Hook F.), has been reported to have therapeutic efficacy against various cancer cells, including prostate cancer, leukemia, and melanoma cells. However, ERα regulation by Celastrol has not been reported. In this study, we investigated the effects of Celastrol on the growth of breast cancer cells. We observed that Celastrol decreased expression of ERα at both the mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Results from a luciferase assay showed that Celastrol decreased the transcriptional activity of ERα. Also, Celastrol treatment inhibited ERα target gene expression, including expressions of cyclin D(1), progesterone receptor (PR), and c-Myb leading to cell cycle arrest and growth inhibition of breast cancer cells. We propose that Celastrol, an anti-cancer drug extracted from natural sources, induces inhibition of cell growth through modulation of ERα in estrogen positive breast cancer cells and is a candidate for use in cancer chemotherapy for human breast cancer.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Cell Nucleus; Cyclin D1; Cytoplasm; Estrogen Receptor alpha; Female; Humans; Pentacyclic Triterpenes; Proto-Oncogene Proteins c-myb; Receptors, Estrogen; RNA, Messenger; Triterpenes

The aim of this study was to investigate the effect of Celastrol on induction of HL-60 cell apoptosis and its possible mechanism. The proliferative activity of HL-60 cells treated with 0.25 - 8.0 μmol/L of Celastrol for 24 - 72 hours was assayed by MTT method, the effects of Celastrol on apoptosis and cell cycle of HL-60 were detected by TUNEL staining and flow cytometry with Annexin V-FITC/PI double labeling, the expression of pAkt and cyclin D1 at protein and gene level in HL-60 cells treated with Celastrol were measured by Western blot and RT-PCR. The results showed that the Celastrol could obviously inhibit the proliferation of HL-60 cells in concentration-and time-dependent manners, the IC₅₀ value of Celastrol for 24 hours was 6.21 ± 0.242 μmol/L. The Celastrol concentration-dependently induced the apoptosis of HL-60 cells, accompanying with morphological changes of apoptotic cells, which may be related with arrest of cells in G₀/G₁ phase. The Celastrol suppressed the expression of pAkt and Cyclin D1 in HL-60 cells to a varying degree which showed obvious concentration-and time-dependent manners. It is concluded that the Celastrol inhibits the proliferation and induced the apoptosis of HL-60 cells. Its mechanism may be related with down-regulation of p-Act and cyclin D1 expressions.

Topics: Apoptosis; Cyclin D1; Down-Regulation; Gene Expression Regulation, Leukemic; HL-60 Cells; Humans; Pentacyclic Triterpenes; Proto-Oncogene Proteins c-akt; Triterpenes