Osteoblast-induced EGFR/ERBB2 signaling in androgen-sensitive prostate carcinoma cells characterized by multiplex kinase activity profiling

Abstract

Bone metastases in prostate cancer are predominantly osteoblastic. To study regulatory mechanisms underlying the establishment of prostate cancer within an osteoblastic microenvironment, human androgen-sensitive prostate carcinoma cells (LNCaP) were treated with culture medium conditioned by human osteoblast-derived sarcoma cells (OHS), and activated signalling pathways in the carcinoma cells were analyzed using microarrays with tyrosine kinase substrates. Network interaction analysis of substrates with significantly increased phosphorylation levels revealed that signalling pathways mediated by EGFR and ERBB2 were activated in LNCaP cells under OHS influence but also by androgen treatment. Activation of EGFR/ERBB2 signalling was also found in LNCaP cells in cocultures with OHS cells or osteoblastic cells that had been differentiated from human mesenchymal stem cells. Our experimental data suggests osteoblast-directed induction of signalling activity via EGFR and ERBB2 in prostate carcinoma cells and may provide a rationale for the use of EGFR or ERBB2 inhibition in systemic prevention or treatment of metastatic prostate cancer in the androgensensitive stage of the disease.

Tumor kinase activity in locally advanced rectal cancer: angiogenic signaling and early systemic dissemination

“…In this study, hypothesizing that hypoxic tumor signaling mediates both radiation resistance and metastatic progression in rectal cancer, and using previously acquired data [8], we endeavored to correlate the individual patient’s tumor tyrosine kinase activity to the DTC status. In two previous works applying the array technology with tyrosine kinase substrates, we were able to calculate basal kinase activity data and correlate with the biological parameters of interest [8, 15]. In the present study, however, after normalization of basal phosphosubstrate level read-outs, no difference was found among the study patients when comparing those with and without DTC (data not shown).…”

Tumor phosphatidylinositol 3-kinase signaling in therapy resistance and metastatic dissemination of rectal cancer: Opportunities for signaling-adapted therapies

“…This may be performed by targeted phosphoproteome investigations with specific antibodies, which in its most simplistic form may be undertaken by western immunoblotting [40,65]. Alternatively, investigations of phenotypic events may be carried out by designated functional bioassays.…”

Biomarker Identification for Prostate Cancer and Lymph Node Metastasis from Microarray Data and Protein Interaction Network Using Gene Prioritization Method

“…Histone deacetylase-1 (HDAC1) is association with SP1 was much weaker in lymph node metastatic than in nonmetastatic prostate cancer [56]. Our experimental data suggests induction of signalling activity via EGFR in prostate tumor cells and may provide a rationale for the use of EGFR inhibition in systemic prevention or treatment of lymph node metastatic [57]. In particular our experiments observed a properly designed inhibitor of nuclear receptor subfamily 5 (NR5A1) may be predicted to have therapeutic utility in the treatment of metastatic lymph node through suppression of androgen receptor.…”