Presentation Authors: Tomoharu Fukumori*, Kei Daizumoto, Megumi Tsuda, Keisuke Ozaki, Yoshito Kusuhara, Hidehisa Mori, Tomoya Fukawa, Yasuyo Yamamoto, Kunihisa Yamaguchi, Masayuki Takahashi, Hiro-omi Kanayama, Tokushima, Japan
Introduction: Castration-resistant prostate cancer (CRPC) has been leading cause of prostate cancer-related death at present. Therefore, improved therapeutic options are needed for men with CRPC and the mechanism of tumor progression and drug resistance should be elucidated. We have found that galectin-3 enhances anti-cancer drug resistance induced by cisplatin or etoposide through the regulation of caspase signaling in prostate cancer. Here, we investigate the effects of galectin-3 for taxane chemotherapy and new promising drug PARP inhibitor in CRPC. We also investigate the tumor progression and drug resistance mechanisms of galectin-3 for CRPC using bioinformatics analysis.
Methods: LNCaP and galectin-3-expressing LNCaP (LNCaP-Gal-3), or PC-3 and galectin-3-knockdown PC-3 (PC3-siGal-3) cells were cultured with androgen-depleted media with 5% charcoal-stripped serum. Cells were treated for 24 hours with mock, docetaxel (1 nM), and olaparib (10 Î¼M). Apoptotic cells were measured by propidium iodide permeability and annexin V binding by FACScan. Gene profile was analyzed by microarray analysis and mRNA expression was confirmed by quantitative PCR. We have combined the bioinformatics analysis using DAVID to assess the galectin-3-induced molecules and pathways for cancer progression.
Results: Galectin-3 significantly suppressed cell apoptosis induced by 1 nM docetaxel or 10 Î¼M olaparib in LNCaP (percent of apoptotic cells in docetaxel: LNCaP 17.4% vs LNCaP-Gal-3 6.8%, olaparib: LNCaP 24.2% vs LNCaP-Gal-3 8.9%, respectively) through the regulation of PI3K and caspase signaling. Based on bioinformatics analysis, galectin-3 expressing cells significantly enhanced PI3K-Akt signaling pathway, rap1 signaling pathway, and TGF-beta signaling pathway by 5 times or more. In LNCaP-Gal-3 and PC-3 cells, galectin-3 upregulated the cell surviving factors such as PI3K and Akt, cell growth factors such as EGF and TGF-beta, bone metastasis-related genes such as RUNK2 and BMP7, and PARP-related genes such as PARP14 which promote survival of cancer cells in agreement with the results of bioinformatics analysis.
Conclusions: The results indicate that galectin-3 is involved in the tumor progression and drug resistance in CRPC by regulating cell surviving signal, cell growth factors, and PARP-related genes. These results suggest that galectin-3 is one of the target molecules for future treatments in patients with CRPC.