The proteins DLK1 and DLK2 modulate NOTCH1-dependent proliferation and oncogenic potential of human SK-MEL-2 melanoma cells

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 gamma-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. (C) 2014 Elsevier B.V. All rights reserved.