Phorbol esters activate proteoglycan metabolism in human colon cancer cells en route to terminal differentiation

Tumor-producing phorbol esters [e.g., 12-O-tetradecanoylphorbol-13-acetate (TPA)] induce changes in a human colon cancer cell line, VACO 10MS, that mimic terminal differentiation: a rapid blockade of DNA replication and cell division, a marked increase in cell adhesion properties with striking changes in morphology, and the acquisition of ion-transporting activities. The present report shows that the triggering of this terminal differentiation sequence by TPA is associated with a rapid release of heparan sulfate proteoglycans from the cell surface that is soon followed by an acceleration of proteoglycan synthesis. The activation of the release mechanism is independent of ongoing protein synthesis, whereas the resynthesis of the proteoglycans requires the production of new proteins. A persistent high rate of proteoglycan synthesis and release appears correlated with the progression of the colon cell into the terminal differentiation state. Bryostatin 1, an agent which has been shown previously to block the TPA-induced terminal differentiation of this cell line, also largely prevents the TPA effects on proteoglycan metabolism. Since both TPA and bryostatin 1 produce their effects through the activation of members of the protein kinase C class of enzymes, it is proposed that the differentiation state of these colon cancer cells may be regulated by a differential activation of isozymes or a ligand-directed phosphorylation of proteins that are involved in proteoglycan metabolism.