Thapsigargin, a histamine secretagogue, is a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type tumor promoter in two-stage mouse skin carcinogenesis

Abstract

Thapsigargin, a hexaoxygenated tetraacylated sesquiterpene lactone, induced irritation of mouse ear and histidine decarboxylase (HDC) activity in mouse skin, but it did not induce ornithine decarboxylase in mouse skin or adhesion of human promyelocytic leukemia (HL-60) cells. Although thapsigargin did not give consistent positive results in a short-term screening system for tumor promoters, it was tested in a two-stage carcinogenesis experiment on mouse skin. The potency of thapsigargin to induce HDC in mouse skin was used to determine the dose in this experiment. Application of 10 micrograms (17 nmol) thapsigargin induced HDC activity of 139 pmol CO2/mg protein per 60 min. Tumors were found in the skin of 53.5% of the mice treated with DMBA plus 5 micrograms (8.5 nmol) thapsigargin in week 22, in none of those treated with thapsigargin alone by week 30. One tumor appeared in 1 of 15 mice treated with DMBA alone in week 21. Thapsigargin cannot bind to the phorbol ester receptor in the particulate fraction of mouse skin and so is classified as a non-12-O-tetradecanoylphorbol-13-acetate (TPA) type tumor promoter. It is a new tumor promoter differing in many respects from the well-defined TPA type tumor promoters. Several naturally occurring analogues of thapsigargin, such as thapsigargicin and thapsitranstagin, might also be new non-TPA type tumor promoters, because thapsigargicin and thapsitranstagin induced irritation of mouse ear and HDC activity in mouse skin.