NOTCH receptors regulate cell proliferation and survival in several types of
cancer cells. Depending on the cellular context, NOTCH1 can function as an oncogene or as a tumor suppressor gene. DLK1 is also involved in the regulation of cell growth and
cancer, but nothing is known about the role of DLK2 in these processes. Recently, the
proteins DLK1 and DLK2 have been reported to interact with NOTCH1 and to inhibit NOTCH1 activation and signaling in different cell lines. In this work, we focused on the role of DLK
proteins in the control of
melanoma cell growth, where NOTCH1 is known to exert an oncogenic effect. We found that human DLK
proteins inhibit NOTCH signaling in SK-MEL-2 metastatic
melanoma cells. Moreover, the proliferation rate of these cells was dependent upon the level of NOTCH activation and signaling as regulated by DLK
proteins. In particular, high levels of NOTCH inhibition resulted in a decrease, whereas lower levels of NOTCH inhibition led to an increase in
melanoma cell proliferation rates, both in vitro and in vivo. Finally, our data revealed additive NOTCH-mediated effects of DLK
proteins and the γ-
secretase inhibitor
DAPT on cell proliferation. The data presented in this work suggest that a fine regulation of NOTCH signaling plays an important role in the control of metastatic
melanoma cell proliferation. Our results open the way to new research on the role of DLK
proteins as potential therapeutic tools for the treatment of human
melanoma.