Protein kinase C alpha plays a critical role in mannosylerythritol lipid-induced differentiation of melanoma B16 cells

Mannosylerythritol lipid (MEL), a novel extracellular glycolipid from yeast , was found to inhibit the proliferation of mouse melanoma B16 cells in a d ose-dependent manner and to induce the apoptosis of B16 cells at concentrat ions higher than 10 mum (Zhao, X., Wakamatsu, Y., Shibahara, M., Nomura, N. , Geltinger, C., Nakahara, T., Murata, T., and Yokoyama, K. K. (1999) Cance r Res. 59, 482-486). We show here that exposure of B16 cells to MEL (5 mum) for 2 days resulted in an increase of the levels of differentiation-associ ated markers of melanoma cells such as melanogenesis and tyrosinase activit y, which were accompanied by morphological changes. The MEL-induced differe ntiation of B16 cells at this concentration was closely associated with arr est of the cell cycle at G, phase, but no significant population of apoptot ic cells was identified. Expression of protein kinase C alpha (PKC alpha) w as enhanced after exposure of B16 cells to MEL for 48 h. Antisense oligodeo xynucleotides against the mouse gene for PKC alpha prevented MEL-induced me lanogenesis in B16 cells. Conversely, the effects of the expression of a co nstitutively active form of PKCa mimicked the effects of MEL on B16 cells. These data suggest that MEL, a yeast-derived glycolipid, triggers the diffe rentiation of B16 melanoma cells through a signaling pathway that involves PKC alpha.