Zinc alpha-2-glycoprotein regulates melanin production by normal and malignant melanocytes

J Invest Dermatol. 2002 Aug;119(2):464-70. doi: 10.1046/j.1523-1747.2002.01813.x.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Melanins / biosynthesis*
  • Melanocytes / metabolism*
  • Melanoma, Experimental / metabolism*
  • Mice
  • Monophenol Monooxygenase / metabolism
  • Seminal Plasma Proteins / physiology*
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Melanins
  • Seminal Plasma Proteins
  • Tumor Necrosis Factor-alpha
  • Zn-alpha-2-glycoprotein
  • Monophenol Monooxygenase