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Prostate cancer is the second most frequently diagnosed cancer of men and the fifth most common cancer overall in the world. This disease is one of the most common non-cutaneous carcinoma of men in Western countries. Prostate cancer patients receiving androgen ablation therapy ultimately develop recurrent castration-resistant prostate cancer within 1-3 years.
Chapter 3-1: We discovered two natural compounds, caffeic acid phenethyl ester (CAPE) and cholestane-3, 5, 6-triol, exhibiting anti-cancer activity against prostate cancer cells. Treatment with CAPE suppressed cell survival and proliferation of castration-resistant prostate cancer (CRPC) cell via induction of G1 or G2/M cell cycle arrest in LNCaP 104-R1, DU-145, 22Rv1, and C4-2 CRPC cells. Our finding suggested that CAPE treatment induced cell cycle arrest and growth inhibition in CRPC cells via regulation of Skp2, p53, p21Cip1, and p27Kip1.
Chapter 3-2: Cholestane-3, 5, 6-triol is one of the most abundant and active oxysterol. Intraperitoneal injection of 1 mg of cholestane-3, 5, 6-triol daily for 14 days caused a 36% reduction in average volume of DU-145 xenograft. Cholestane-3, 5, 6-triol selectively suppressed proliferation of prostate cancer cells compared to normal prostate epithelial cells with IC50 ranging from 12-31 M. Cholestane-3, 5, 6-triol caused apoptosis, G1 cell cycle arrest, loss of -actin, and redistribution of -tubulin in prostate cancer cells. Our observations suggested that cholestane-3, 5, 6-triol and CAPE are potential chemotherapy agents for advanced prostate cancer.
Chapter 3-3: Androgen receptor (AR) plays essential role during development and progression of prostate cancer. However, the role of AR on prostate cancer metastasis is not fully understood. We observed that re-expression of AR, which locates in cytoplasmic in the absence of androgen, suppressed cell motility, migration, and invasion of PC-3 cells as determined by wound healing assay and transwell assay. Migration and invasion of PC-3 and PC-3AR cells was promoted by EGF or IGF-1 but was suppressed by Casodex. Re-expression of AR reduced activity of MMP-2 and MMP-9 in PC-3 cells. Our observations suggested that re-expressing AR suppresses migration and invasion of PC-3 cells via regulation of EMT marker proteins and MMP activity.
Chapter 3-4: Online database of clinical samples, including PubMed GEO profile or Oncomine, indicated that Akt3 mRNA expression level was higher in primary prostate tumors as compared to the normal prostate tissues. Immunohistochemical staining of 65 clinical samples revealed that Akt3 protein expression was higher in prostate tumors of stage I, II, III as compared to nearby normal tissues. Plasmid overexpression of Akt3 promoted cell proliferation of LNCaP, PC-3, DU-145, and CA-HPV-10 human prostate cancer cells, while knockdown of Akt3 by siRNA reduced cell proliferation in these cancer cells. Our observations implied that expression of Akt3 provides growth advantage for prostate cancer cells and Akt3 may be a potential therapeutic target for prostate cancer treatment.
We discovered that PI3/AKT kinase signaling pathway and androgen receptors (AR) play essential roles in regulation of proliferation and metastasis of prostate cancer cells. AKT3 promotes proliferation bur suppresses migration and invasion of prostate cancer cells. AR seems to be a tumor suppressor on prostate cancer metastasis. We also identified natural compounds CAPE and cholestane-3beta, 5alpha, 6beta-triol to be potential therapeutic agents for castration-resistant prostate cancer (CRPC) cells. In conclusion, our studies revealed potential therapeutic targets and treatments for advanced PCa | en_US |