Yi Lu

BACKGROUND: Monocyte chemotactic protein-1 (MCP-1) plays a key role in the recruitment and activation of monocytes during inflammation. Increased MCP-1 serum levels in patients with various cancers were correlated with advanced stage. Here, we evaluated the role of MCP-1 on prostate cancer (CaP) cell proliferation and invasion. METHODS: Expression of MCP-1 in tissue specimens was analyzed by immunohistochemical staining. MCP-1 production was determined by ELISA in conditioned media collected from primary prostate epithelia (PrEC), LNCaP, C4-2B, PC3 cells, and hFOB. Cell proliferation and invasion were assayed by MTS assay and invasion chambers. RESULTS: All CaP cells, as well as hFOB, produced high amount of MCP-1 compared to PrEC cells. MCP-1 expression levels were associated with advanced pathologic stage. MCP-1 induced proliferation and invasion of CaP cells and this was abolished partially either by CCR2 antagonist or PI3 Kinase inhibitor. CONCLUSION: MCP-1 acts as a paracrine and autocrine factor for CaP growth and invasion.

While the roles of the mammalian target of rapamycin (mTOR) signaling in regulation of cell growth, proliferation, and survival have been well documented in various cell types, its actions in osteoblasts are poorly understood. In this study, we determined the effects of rapamycin, a specific inhibitor of mTOR, on osteoblast proliferation and differentiation using MC3T3-E1 preosteoblastic cells (MC-4) and primary mouse bone marrow stromal cells (BMSCs). Rapamycin significantly inhibited proliferation in both MC-4 cells and BMSCs at a concentration as low as 0.1 nM. Western blot analysis shows that rapamycin treatment markedly reduced levels of cyclin A and D1 protein in both cell types. In differentiating osteoblasts, rapamycin dramatically reduced osteoblast-specific osteocalcin (Ocn), bone sialoprotein (Bsp), and osterix (Osx) mRNA expression, ALP activity, and mineralization capacity. However, the drug treatment had no effect on osteoblast differentiation parameters when the cells were completely differentiated. Importantly, rapamycin markedly reduced levels of Runx2 protein in both proliferating and differentiating but not differentiated osteoblasts. Finally, overexpression of S6K in COS-7 cells significantly increased levels of Runx2 protein and Runx2 activity. Taken together, our studies demonstrate that mTOR signaling affects osteoblast functions by targeting osteoblast proliferation and the early stage of osteoblast differentiation.

further increased ROS generation and promoted cyst growth, whereas pharmacological induction of NRF2 reduced ROS production and slowed cystogenesis and disease progression. Mechanistically, pharmacological induction of NRF2 remodeled enhancer landscapes and activated NRF2-bound enhancer-associated genes in ADPKD cells. The activation domain of NRF2 formed phase-separated condensates with MEDIATOR complex subunit MED16 in vitro, and optimal Mediator recruitment to genomic loci depended on NRF2 in vivo. Together, these findings indicate that NRF2 remodels enhancer landscapes and activates its target genes through a phase separation mechanism and that activation of NRF2 represents a promising strategy for restoring redox homeostasis and combatting ADPKD.