Research On Mechanism Of Celastrol On SENP1 In Human Prostate Cancer Cells

Worldwide incidence of prostate cancer ranks the second place after lung cancer, and has a gradually increase trend with age in its incidence. The incidence of prostate cancer in China and abroad is very different. Europe and the United States have a higher prevalence, incidence is relatively low Orient. However, in recent years, the incidence in our country on the rise. The mainstay of treatment for advanced PCA remains androgen ablation therapy as originally introduced in the early 1940s. Although the vast majority of prostate cancer is hormone-sensitive initially, some patients who are undergoing such therapy can easily transform to hormone-refractory prostate cancer (hormone-refractory prostate cancer (HRPC)) or hormone refractory prostate cancer (androgen-independent prostate cancer, AIPC) over time. Once the cancer progresses to HRPC or AIPC stage, the cancer will spread very quickly and hormone therapy is no longer curative. From this point on, reliable treatment strategies available are limited.SUMO-specific protease 1 SENP1 is over-expressed in prostate cancer tissues and cells. meanwhile, transgenic mice indicates that over-expression of SENP1 leads to the development of prostatic intraepithelial neoplasia at an early age, SENP1 has become a marker of prostate cancer development and potential therapeutic target for prostate cancer. Designing therapeutic agents targeting SENP1 is more effective than androgen ablation therapy in the treatment of advanced Pca, because SENP1 could regulate the activity of androgen receptor (AR), which would not lead to the development of androgen-independent cancer. It is important to study the influence of drugs on SENP1 expression in prostate cancer.By using trypan blue staining, we comprehensively study the growth inhibition effect of celastrol on two human prostate cancer cell lines including AR dependent LNCaP cells and AR independent PC-3 cells, then we detect the change of over-expressed SENP1 mRNA leves in both cells after celastrol treatment utilizing representive real-time quantitative PCR technology. Results show that 1μM celastrol has a strong inhibititon effect on prostate cancer cells after exactly the first day of treatment, both two cell lines have stopped growth completely, LNCaP cells are more sensitive to celastrol than PC-3 cells. When considering effect of celastrol on down-regulating SENP1 mRNA levels, we found, exposure to 0.1μM and 1μM celastrol for 48h, SENP1 mRNA levels in PC-3 cells were almost decreased by 2 times, much more than 24h,this show us that celastrol have Dose-effect and time-effect .But SENP1 mRNA levels in LNCaP cells were decreased by not so much no matter exposure to 0.1μM or 1μM celastrol ,and this can be explained by the higher SENP1 mRNA levels in PC-3 cells than in LNCaP cells. Predecessors have been confirmed that SENP1 mRNA expression in LNCaP cells is 2.5 times higher than in normal prostatic epithelial cells RWPE1, so down-regulated SENP1 mRNA levels in PC-3 cells may equal to that in normal prostate epithelial cells when refer to the dose-effect of celastrol .In summary, celastrol inhibits growth of androgen-independent cells. In addition, it reduces SENP1 mRNA expression to that in normal cells when refer to the dose-effect and time-effect, suggesting that its application value in the treatment of hormone-refractory prostate cancer.