Superoxide and hydrogen peroxide in relation to mammalian cell proliferation.

A wide variety of normal and malignant cell types generate and release superoxide or hydrogen peroxide in vitro either in response to specific cytokine/growth factor stimulus or constitutively in the case of tumour cells. These species at submicromolar levels appear to act as novel intra and intercellular "messengers" capable of promoting growth responses in culture. The mechanisms may involve direct interaction with specific receptors or oxidation of growth signal transduction molecules such as protein kinases, protein phosphatases, transcription factors, or transcription factor inhibitors. It is also possible that hydrogen peroxide may modulate the redox state and activity of these important signal transduction proteins indirectly through changes in cellular levels of GSH and GSSG. Critical balances appear to exist in relation to cell proliferation on one hand and lipid peroxidation and cell death on the other. Progression to a more prooxidant state whilst initially leading to enhanced proliferative responses results subsequently in increased cell death.