| Prostate cancer is one of the common diseases in the male reproductive system tumor, its incidence and mortality showed an increased trend year by year, the trend is especially obvious in China. In the treatment of prostate cancer, the early stage patients were treated by resection of the prostate with auxiliary radiation therapy; for the late, mainly by hormone therapy, but prostate cancer will become gradually hormonal refractory from hormone-independent after a period of treatment, it makes treatment more difficult. Finally when deprivation therapy or traditional hormone therapy failed, chemotherapy has to the only treatment. However, many times treatment by chemotherapy can make patients develop resistance to chemotherapy drugs, leading to poor overall curative effect of chemotherapy. Therefore, looking for more effective chemotherapy drugs is the new trend for the treatment of prostate cancer.Due to drug discovery and development are expensive and time-consuming process, as well as the idea of approved drugs new-using offer us a new shortcut, so in the early days we used the established the clinical pharmacy of Johns Hopkins university for high-throughput screening and identified one antibiotic drug named Clofoctol, which has been used in clinical treatment of respiratory tract infection, it could inhibit prostate cancer hormone-sensitive cell line PC3 proliferation. Given monotherapy have side effects and the advantage of drug combination for tumor therapy, we chosen about forty small molecule drugs for inhibiting prostate cancer cells, which have entered clinical application, and combination with Clofoctol to treat PC3 cells respectively, then according to Chou-Talalay formula and dose-response method, we found that Clofoctol and Sorafenib could inhibit PC3 cells proliferation synergistically. Sorafenibis a kind of multiple-target kinase inhibitor, approved by the FDA for using in the treatment of advanced renal cell carcinoma and liver cancer, now a large number of studies have confirmed Sorafenib could produce depression effect on the proliferation of prostate cancer.Based on PC3 cells model, we studied the synergy mechanism of the combination Clofoctol and Sorafenib. Through cell apoptosis and cell cycle detection methods, as well as Western blot and qRT-PCR et al, we determined 10 μM Clofoctol combined with 6 μM Sorafenib could synergistically make 78.84% cells stuck in the G1 phase, and the apoptosis rate up to 16.65%,which was higher than the rate Sorafenib or Clofoctol produced alone; qRT-PCR results showed that DDIT3/CHOP, GADD34, ATF6 and ATF4 mRNA expression levels increased obviously and the corresponding Western blot results showed that DDIT3/CHOP and ATF4 protein levels increased significantly at 8 hours, and XBP1 was obviously cut into XBP1 s, the activated transcription factors when treatment with the combination for 24 hours. That is, Clofoctol and Sorafenib combined activate the IRE-1a and ATF6 pathways of ER-stress. Next the phenomena what we observed after Clofoctol treated PC3 cells were endoplasmic reticulum vacuolization and ubiquitin-protein accumulation, which were similar with the effects of using RNAi of VCP/p97. In view of the VCP/p97 plays an important role in endoplasmic reticulum associated proteasome system. Therefore, we speculated that Clofoctol might work on VCP/p97 and inhibit its function.Based on another research direction of our laboratory, we also conducted the associated analysis on microRNA polymorphisms and lung cancer susceptibility. Lung cancer has the fastest growing incidence and mortality; it is the one of biggest threat to people’s health and life, and genetic factor is one of the important causes of lung cancer. A growing number of studies showed that microRNAs play ontogenesis or tumor suppressor genes’ function, and microRNA single nucleotide polymorphisms have some certain correlation with tumor susceptibility. Through our statistical analysis and literature review early, we identified miR-4293 rs12220909 as the research object, proposed by case-control research to analyze the relationship between mirSNPs and lung cancer susceptibility in Chinese people.In term of 998 lung cancer cases and 1471 normal control cases, the results showed that there was a remarkable relevance between miR-4293 rs12220909 and lung cancer risk: mutation genotype GC/CC can significantly reduce lung cancer risk(OR = 0.687; 95% CI = 0.564 0.837) and alleles C is a protective factor in lung cancer susceptibility(OR = 0.734; 95% CI = 0.616 0.874);Genetic model for stratified analysis found that the GC genotypes at the age of 62 or higher, < 62 years old, male, smoking, non-smoking, lung squamous carcinoma and lung adenocarcinoma all could reduce the risk of lung cancer. Next, we studied the mechanism how mi R-4293 rs12220909 reduce the risk of lung cancer, found that wild type miR-4293 may regulate tumor suppressor genes PRKAA1 and ADAMTSL3 to enhance lung cancer susceptibility, in other words it may plays a promoting role in the occurrence and development of lung cancer. |
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