Abstract
Prostate cancer bone metastases are characterized by their ability to induce osteoblastic lesions and local bone formation. It has been suggested that bone metastatic prostate cancer cells are osteomimetic and capable of expressing genes and proteins typically expressed by osteoblasts. The ability of preosteoblasts to differentiate and express osteoblastic genes depends on several pathways, including Notch and MAPK. Here we show that notch1 expression is increased 4-5 times in C4-2B and MDA PCa 2b cells (osteoblastic skeletal prostate metastatic cancer cell lines) when compared with nonskeletal metastatic cell lines (LNCaP and DU145). Notch1 ligand, dll1, is expressed only in C4-2B cells. Immunohistochemical studies demonstrate that Notch1 is present in both human clinical samples from prostate cancer bone metastases and the C4-2B cell line. To determine whether prostate cancer bone metastases respond to osteogenic induction similar to osteoblasts, C4-2B cells were cultured in osteogenic medium that promotes mineralization. C4-2B cells mineralize and express HES-1 (a downstream target of Notch), an effect that is completely inhibited by L-685,458, a Notch activity inhibitor. Furthermore, osteogenic induction increases ERK activation, runx2 expression, and nuclear localization, independent of Notch signaling. Finally, we show that Notch and ERK activation are essential for Runx2 DNA binding activity and osteocalcin gene expression in C4-2B cells in response to osteogenic induction. These studies demonstrate that prostate cancer bone metastatic cell lines acquire osteoblastic properties through independent activation of ERK and Notch signaling; presumably, both pathways are activated in the bone microenvironment.
Highlights
Normal and neoplastic, have the potential to stimulate new bone formation by effects on both osteoblasts and osteoclasts
It has been shown that the osteoblastic C4-2B prostate cancer cell line (LNCaP derivative cell line) [22] has an increased expression of Runx2 [10], whereas the osteolytic PC3 cell line expresses transcriptionally active Cbaf1 as shown by its ability to bind to OSE2 on the osteocalcin promoter [11]
We hypothesize that the activation of Notch in prostate cancer metastases in the bone microenvironment leads to a cascade of signaling events, which results in a unique pattern of gene expression similar to that seen in mature osteoblasts
Summary
Normal and neoplastic, have the potential to stimulate new bone formation by effects on both osteoblasts and osteoclasts. There is increasing evidence that prostate cancer bone metastases express genes and proteins typically associated with osteoblasts, including RANK ligand, osteoprotegerin [8], sialoproteins, osteopontin [9], Runx (Runt-related transcription factor 2) [10], and osteocalcin [11]. It has been shown that the osteoblastic C4-2B prostate cancer cell line (LNCaP derivative cell line) [22] has an increased expression of Runx2 [10], whereas the osteolytic PC3 cell line expresses transcriptionally active Cbaf as shown by its ability to bind to OSE2 on the osteocalcin promoter [11] This suggests that Runx expression/activity could play a role in the modulation of gene expression in prostate cancer metastases. Our results suggest that Notch activation plays a critical role in the ability of prostate cancer metastases to acquire “osteoblast-like” properties
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