Gap junctions are intercellular plasma membrane domains containing channels that mediate transport of
ions, metabolites and small signaling molecules between adjacent cells. Gap junctions play important roles in a variety of cellular processes, including regulation of cell growth and differentiation, maintenance of tissue homeostasis and embryogenesis. The constituents of gap junction channels are a family of trans-
membrane proteins called
connexins, of which the best-studied is
connexin 43.
Connexin 43 functions as a
tumor suppressor protein in various tissue types and is frequently dysregulated in human
cancers. The
pesticide ioxynil has previously been shown to act as an
endocrine disrupting chemical and has multiple effects on the thyroid axis. Furthermore, both
ioxynil and its derivative
ioxynil octanoate have been reported to induce
tumors in animal bioassays. However, the molecular mechanisms underlying the possible tumorigenic effects of these compounds are unknown. In the present study we show that
ioxynil and
ioxynil octanoate are strong inhibitors of
connexin 43 gap junction channels. Both compounds induced rapid loss of
connexin 43 gap junctions at the plasma membrane and increased
connexin 43 degradation.
Ioxynil octanoate, but not
ioxynil, was found to be a strong activator of ERK1/2. The compounds also had different effects on the phosphorylation status of
connexin 43. Taken together, the data show that
ioxynil and
ioxynil octanoate are potent inhibitors of intercellular communication via gap junctions.