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.
Hale
Laura P
LP
Department of Pathology and the Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710, USA. laura.hale@duke.edu
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