Zinc alpha-2-glycoprotein regulates melanin production by normal and malignant melanocytes.
Zinc alpha-2-glycoprotein is secreted by a variety of normal and malignant epithelial cells and overexpression by tumors has been implicated in cancer cachexia. To investigate biologic properties of zinc alpha-2-glycoprotein further, stable transfectants of recombinant human zinc alpha-2-glycoprotein were created in the B16F10 murine melanoma cell line. Both B16-recombinant human zinc alpha-2-glycoprotein clones with strong expression of zinc alpha-2-glycoprotein and vector-transfected B16 cells treated with exogenous zinc alpha-2-glycoprotein had decreased melanin production in vitro. Furthermore, B16-recombinant human zinc alpha-2-glycoprotein clones formed amelanotic tumors in vivo, despite their melanin production in vitro. Although no qualitative differences in tyrosinase mRNA expression could be detected by reverse transcription-polymerase chain reaction, B16-recombinant human zinc alpha-2-glycoprotein tumors had decreased levels of tyrosinase protein and minimal tyrosinase activity. Purified zinc alpha-2-glycoprotein also decreased tyrosinase activity in vector-transfected B16 tumor sections in vitro. Taken together, these studies demonstrate that zinc alpha-2-glycoprotein inhibits melanin production by B16 melanoma cells via post-transcriptional effects on tyrosinase protein. As zinc alpha-2-glycoprotein decreases melanin synthesis more strongly in vivo than in vitro, however, it is likely that zinc alpha-2-glycoprotein affects melanin synthesis through indirect mechanisms as well. Zinc alpha-2-glycoprotein also inhibits melanin production by melan-A primary melanocytes in vitro. As zinc alpha-2-glycoprotein is normally produced by epidermal keratinocytes, these studies raise the possibility that epidermal-derived zinc alpha-2-glycoprotein may play a part in normal regulation of melanin production in vivo, in addition to its previously described role in cancer cachexia.
Department of Pathology and the Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710, USA. laura.hale@duke.edu
Laura P
LP
Hale
D000818:Animals; D002460:Cell Line; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism*; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism; D029589:Seminal Plasma Proteins / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000090203:Zn-Alpha-2-Glycoprotein
D008543:Melanins; D029589:Seminal Plasma Proteins; D014409:Tumor Necrosis Factor-alpha; D000090203:Zn-Alpha-2-Glycoprotein; D014442:Monophenol Monooxygenase