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Ability of the non‐phorbol ester‐type tumor‐promoter thapsigargin to mimic the stimulatory effects of 12‐0‐tetradecanoylphorbol‐13‐acetate on ornithine decarboxylase activity, hydroperoxide production, and macromolecule synthesis in mouse epidermis In vivo
Author(s) -
Perchellet Elisabeth M.,
Gali Hala U.,
Gao Xiao Mei,
Perchellet JeanPierre
Publication year - 1993
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910550626
Subject(s) - ornithine decarboxylase , 12 o tetradecanoylphorbol 13 acetate , protein kinase c , tetradecanoylphorbol acetate , dna synthesis , tumor promotion , thapsigargin , cycloheximide , ionomycin , biochemistry , phorbol , biology , medicine , microbiology and biotechnology , endocrinology , chemistry , protein biosynthesis , enzyme , endoplasmic reticulum , intracellular , dna , carcinogenesis , phorbol ester , gene
Abstract The biochemical effects of the non‐12‐0‐tetradecanoylphorbol‐13‐acetate (TPA)‐type tumor promoter thapsigargin (TG), which does not bind to the phorbol‐ester receptor, or activate protein kinase C (PKC) or increase inositol polyphosphates, were characterized in mouse epidermis in vivo . The cold scraping method is required to detect the induction of ornithine decarboxylase (ODC) activity by TG, a response much smaller than that caused by TPA and with a different time course, TG pre‐treatments do not alter or cause a refractory state against ODC induction by TPA. But TG stimulates hydroperoxide (HPx) production and RNA, protein, and DNA synthesis almost as much as TPA. Moreover, the sequential effects of TG and TPA on DNA synthesis are identical: early inhibition at 8 hr followed by maximal stimulation at 16‐32 hr. TG‐stimulated HPx production requires protein synthesis and xanthine oxidase, phospholipase A2, and lipoxygenase activities but not RNA and DNA synthesis, and cyclooxygenase and protease activities. The HPx response to TG is not mimicked by the PKC activator prostratin or inhibited by pre‐treatments with prostratin or specific PKC inhibitors. However, the Ca2 + ‐ATPase inhibitor cyclopiazonic acid and the Ca 2+ ionophore and weak ODC inducer A23187 mimic remarkably the HPx responses to TG and TPA. Since TG and A23187 are known to be, respectively, weak and incomplete tumor promoters as compared with TPA, the present results suggest that the HPx responses common to Ca 2+ ‐mobilizing and TPA‐ or non‐TPA‐type agents are insufficient to achieve tumor promotion in the absence of major ODC induction.