Caffeic Acid Phenethyl Ester Causes p21Cip1 Induction, Akt Signaling Reduction, and Growth Inhibition in PC-3 Human Prostate Cancer Cells

Caffeic acid phenethyl ester (CAPE) treatment suppressed proliferation, colony formation, and cell cycle progression in PC-3 human prostate cancer cells. CAPE decreased protein expression of cyclin D1, cyclin E, SKP2, c-Myc, Akt1, Akt2, Akt3, total Akt, mTOR, Bcl-2, Rb, as well as phosphorylation of Rb, ERK1/2, Akt, mTOR, GSK3α, GSK3β, PDK1; but increased protein expression of KLF6 and p21Cip1. Microarray analysis indicated that pathways involved in cellular movement, cell death, proliferation, and cell cycle were affected by CAPE. Co-treatment of CAPE with chemotherapeutic drugs vinblastine, paclitaxol, and estramustine indicated synergistic suppression effect. CAPE administration may serve as a potential adjuvant therapy for prostate cancer

Modulation of liver X receptor signaling as a prevention and therapy for colon cancer

[[abstract]]Liver X receptors (LXRalpha and LXRbeta) are members of the nuclear receptor family and are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, and Alzheimer's disease. Recently we and other groups observed that LXR agonists suppressed proliferation of multiple human cancer cell lines in vitro as well as suppressed the growth and progression of prostate tumor xenografts in nude mice. LXR agonists appear to cause G1 cell cycle arrest in cancer cells by reducing the protein expression level of Skp2, cyclin A2, cyclin D1, and the phosphorylation of Rb, while increasing the protein expression level of cell cycle inhibitor p27(Kip1) and p53. LXR agonist also suppressed the oncogenic activity of beta-catenin, an important regulator in Wnt signaling, as well as the proliferation in human colon cancer cells. Phytosterols, the plant equivalent of mammalian cholesterol, have been shown to be agonists for LXRs. Intake of phytosterol-rich diets reduced the incidence of colon cancer. We therefore propose that activation of LXR signaling via treatment with LXR agonists or intake of phytosterols-rich diets can reduce the incidence and suppress the tumor growth of colon cancer

Non-Canonical Wnt receptor ROR2 suppresses prostate cancer metastasis

[[abstract]]Prostate cancer (PCa) ranks the 5th most common cancer in the world. Receptor tyrosine-kinase like orphan receptor 2 (ROR2) is a regulator of non-canonical Wnt signaling. Expression of mRNA and protein of ROR2 was analyzed in clinical samples with qRT-PCR and IHC staining. Tranwell assays and wound healing assay were performed to determine the roles of ROR2 on migration and invasion of PCa cells. Micro-Western Array MWA platform was introduced to determine downstream signaling network regulated by ROR2. Analysis of ROR2 gene expression level in a total of 249 normal prostate tissues, benign prostate hyperplasia BPH, and prostate tumors revealed that ROR2 mRNA level is the lowest in metastatic PCa. IHC staining analysis of 48 PCa tissues indicated that ROR2 expression inversely correlated to aggressiveness of PCa...

Androgen suppresses proliferation of castration-resistant LNCaP 104-R2 prostate cancer cells through androgen receptor, Skp2, and c-Myc

[[abstract]]Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. To study if termination of long-term androgen ablation and restoring testosterone level may suppress the growth of relapsed hormone-refractory prostate tumors, we implanted testosterone pellets in castrated nude mice carrying androgen receptor (AR)-positive LNCaP 104-R2 cells, which relapsed from androgen-dependent LNCaP 104-S cells after long-term androgen deprivation. 104-R2 tumor xenografts regressed after testosterone pellets implant. 24 out of 33 tumors adapted to elevation of testosterone level and relapsed as androgen-insensitive tumors. Relapsed tumors (R2Ad) expressed less AR and prostate-specific antigen (PSA). We then study the molecular mechanism lying underneath the androgenic regulation of prostate cancer cell proliferation. Androgen suppresses proliferation of 104-R2 by inducing G1 cell cycle arrest via reduction of Skp2 and c-Myc, and induction of p27(Kip1) . 104-R2 cells adapted to androgen treatment and the adapted cells, R2Ad, were androgen-insensitive cells with slower growing rate and low protein level of AR, high levels of c-Myc and Skp2, and low levels of p27(Kip1) . Nuclear AR and PSA expression is present in 104-R2 cells but not R2Ad cells when androgen is absent. Overexpression of AR in R2Ad cells regenerated an androgen-repressed phenotype, while knockdown of AR in 104-R2 cells generated an androgen-insensitive phenotype. Overexpression of Skp2 and c-Myc in 104-R2 cells blocked the growth inhibition caused by androgens. We concluded that androgens cause growth inhibition in LNCaP 104-R2 prostate cancer cells via AR, Skp2, and c-Myc

Histone demethylase KDM4C is a novel oncogene and prognostic biomarker for prostate cancer

[[abstract]]Background: Prostate cancer (PCa) is the 5th most common cancer overall in the world. Epigenetic alterations is involved in the development or progression of cancer via regulation of histone modifications. Histone lysine demethylases KDM4C is androgen receptor (AR) co-regulator and modulate AR-mediated transcription. Expression of KDM4C was reported to be higher in castration-resistant prostate cancer (CRPC). Methods: Role of KDM4C in cell proliferation and docetaxel-resistance was determined using MTT assay and 96-well proliferation assay. Effects of KDM4C on PCa migration and invasion was determined by trasnwell assay. Role of KDM4C on cancer stemness was examined using cell sorter. Inhibitory role..

Targeting Akt signaling for treatment of advanced prostate cancer cells with caffeic acid phenethyl ester

[[abstract]]Prostate cancer is one of the most common non-cutaneous carcinomas of men in Western countries. More than 80% of patients die from prostate cancer bone metastases. Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, most prostate cancer patients receiving the androgen ablation therapy will ultimately develop recurrent, castration-resistant tumors within 1-3 years after treatment. The median overall survival time is 1-2 years after tumor relapse. Chemotherapy is usually applied for treatment of metastatic hormone-refractory prostate cancer. However, they showed little effect on prolonging survival. Undesired side effects of these chemotherapeutic agents include toxic deaths, strokes, thrombosis, neutropenia, edema, dyspnea, malaise, and fatigue. Combining chemotherapeutic drugs with natural compounds of anticancer activities may reduce the dosage of chemotherapeutic drugs needed. More than 80% of prostate tumors acquire mutation or deletion of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling, indicating that inhibition of PI3K/Akt might be a potential therapy for advanced prostate tumors. Our observations indicated that caffeic acid phenethyl ester (CAPE) treatment suppressed proliferation of different prostate cancer cell lines as well as tumor growth of PC-3 xenograft. CAPE treatment disturbed cell cycle progression in human prostate cancer cells. CAPE decreased protein expression of cyclin D1, cyclin E, SKP2, c-Myc, Akt1, Akt2, Akt3, total Akt, mTOR, Bcl-2, Rb, as well as phosphorylation of Rb, ERK1/2, Akt, mTOR, GSK3α, GSK3β, PDK1. In contrast, CAPE increased protein expression of KLF6 and p21Cip1. Combination of CAPE with chemotherapeutic drugs produced synergistic suppression effects. Our studies indicated that CAPE treatment affects Akt signaling in prostate cancer cells and CAPE administration may thus serve as a potential adjuvant therapy for advanced prostate cancer

KDM4C: A novel oncogene and prognostic biomarker for prostate cancer

[[abstract]]Human histone lysine demethylases 4C is an AR co-regulator. We investigated the role of KDM4C in prostate cancer (PCa). Analysis of both Oncomine gene datasets and commercial tissues array, we observed that the mRNA and protein expression of KDM4C is highest in metastatic prostate cancer tissues. PCa patients with higher KDM4C expression level correlate to worse prognosis. Knockdown of KDM4C in PCa cells reduced cell proliferation, soft agar colony formation, migration, and invasion as well as suppressed tumor growth in PCa orthotopic model in nude mice. Prostate cancer stem cells and docetaxel resistant PCa cells express higher KDM4C proteins. Micro Western Array (MWA) is an antibody-based high throughput protein array allowing detecting protein expression level or phosphorylation status change of 96-192 different antibodies in 6 to 15 samples simultaneously. MWA analysis indicated that reduction of KDM4C affected protein expression of cell cycle regulatory proteins, cMyc, DKK3, and EMT marker proteins. Our study indicated that KDM4C is a novel oncogene in PCa and KDM4C may serve as a prognostic biomarker for clinical outcome of PCa