Endothelin signaling in osteoblasts: global genome view and implication of the calcineurin/NFAT pathway

Patients with prostate cancer develop osteoblastic metastases when tumor cells arrive in the bone and stimulate osteoblasts by secreting growth-promoting factors. Endothelin 1 (ET-1) is believed to be a key factor in promoting osteoblastic metastasis. Selective blockade of the ET(A) receptor is an established strategy in the development of cancer therapeutics. However, the molecular mechanisms whereby prostate cancer promotes abnormal bone growth are not fully understood. In this study, we have applied genomic approaches to elucidate the molecular mechanism of stimulation of osteoblasts by ET-1. To examine the ET-1 axis, we generated genomic signatures for osteoblasts treated with ET-1, in the presence and absence of a selective ET(A) antagonist (ABT-627). The ET-1 signature was comprised of several motifs, such as osteoblastic differentiation, invasion, and suppression of apoptosis. The signature also pointed at possible activation of the calcineurin/NFAT pathway. We showed that ET-1 activates calcineurin and causes nuclear translocation of NFATc1, implicating the pathway in the ET-1-mediated stimulation of osteoblasts. We also showed that ET-1 inhibits apoptosis in osteoblasts, implying that the suppression of apoptosis may be an important factor in the promotion of osteoblastic growth by ET-1.