A Preliminary Research On The Mechanism Of Drug Resistance Hormone Refractory Prostate Cancer

Prostate cancer is a most common malignant tumor in males. The mortality in male malignant tumors ranked the second. Chinese men’s prostate cancer incidence is lower than that in some western countries, but in recent years,due to changes in the environment and other factors makes the incidence of prostate cancer rate increasing.Prostate cancer occurrence development process mainly depends on the androgen receptor. Therefore, androgen deprivation therapy become the third standard therapy in addition of surgical therapy and radiotherapy. But prostate cancer patients accepted18-24 months of androgen deprivation therapy, most patients are no longer valid into hormone refractory prostate cancer(HRPC), And easy to metastasize to bone, and mortality increases greatly, bone metastasis after treatment has become very difficult.Thus for HRPC transformation mechanism research has become a hot research topic in the treatment of prostate cancer at home and abroad. But hormone resistant prostate cancer transformation process involves many factors, has been found with a large amount of prostate cancer generated resistance related genes and signal pathways can be fully described the mechanism of drug resistance, which need further study. In addition, most of the HRPC research are in DU145, PC3 hormone refractory cells as a model for the expression of endogenous androgen receptors are not completely mimic the clinical HRPC transformation process, therefore, the information obtained is very limited and incomplete, the formation mechanism of HRPC is still a great challenge.This study selected with human prostate cancer differentiation characteristics and strong androgen dependent cell line LNCa P. Through training environment of androgen deprivation induced the androgen resistance LNCa P-HR cell model,because of its simulated clinical prostate cancer received hormone deprivation therapy to change for hormone refractory process, so it can be used to explore the HRPC transition of cytology and molecular biology mechanism.In LNCa P, LNCa P-HR cell model for gene expression profile analysis using gene chip technology, results are obtained for the expression of genes that are upregulated in 20, 206 down regulated genes. Of difference expression gene functions are classified and analyzed, and the results showed the upregulation of genes mainlyinvolves intra cellular gene regulation and expression, metabolism, the variable shear function, whereas the expression down regulated genes mainly and the membrane protein and transmembrane protein, ion binding and intercellular signal transduction and gene expression regulation function. Combined with biological process,differentially expressed gene function and published literature, analysis possible signal transduction pathway for explore the mechanism of the occurrence of HRPC to provide direction.According to the microarray bioinformatics analysis results,validation the key protein of the PI3 K / AKT pathway and MAPK / ERK and MAPK/P38 etc. pathway.Western blot results showed that, LNCa P compared with LNCa P-HR,NF kappa B downstream of Akt protein expression increased, but the expression of AKT and P-AKT protein were no significantly changes, suggesting that NF-κB may be one of the key site of steroid resistant related signal pathway, but it not activation of the PI3K/ AKT signaling pathway may exist in other signaling pathway activated.MAPK signal pathway key protein Western blot results showed that compared to LNCa P-HR in LNCa P,ERK P-ERK protein expression had no obvious change, P38 and P-P38 expression increased significantly, suggest that MAPK / ERK signal pathway in HRPC transformation process has not function, and signal MAPK/P38 pass road in the process of LNCa P changes to LNCa P-HR may play an important role.LNCa P and LNCa P-HR cells as hormone dependent and hormone refractory prostate cancer model, for a variety of small molecule inhibitors and natural product screening,lycopene as a natural carotenoid pigment, can significantly inhibit prostate cancer cell, especially the proliferation of hormone refractory cells. Cell proliferation assay showed that, 80 μmol / L, lycopene can inhibit the proliferation of LNCa P cells,and 40 μmol / L,lycopene can effectively inhibit cell LNCa P-HR, suggesting that lycopene can more effectively inhibit hormone refractory prostate cancer cell growth.Further explore the related signal pathway of lycopene, the results show that lycopene can up regulate the expression of LNCa P and LNCa P-HR cells’ P38, P-P38 proteins,but there is no effect on the expression of ERK,AKT,NF-κB proteins, the prompt lycopene may through MAPK/P38 signaling pathway play anti-tumor effect and this phenomenon is consistent with the possible signal pathway of the above HRPC transformation.There are reports MAPK/P38 signaling pathway in ovarian cancer and themechanism of drug resistance of breast cancer play an important role, but in the mechanism of multidrug resistance in prostate cancer has not been reported yet. The treatment of HRPC mechanism research and HRPC provides a new direction.